Osteoporosis: Clinical Guidelines

List of Abbreviations

BP – bisphosphonates

WHO – World Health Organization

GCO – glucocorticoid-induced osteoporosis

CI – confidence interval

CHD – coronary heart disease

QCT – quantitative computed tomography

CT – computed tomography

CEE – conjugated equine estrogens

MHT – menopausal hormone therapy

BMD – bone mineral density

MRI – magnetic resonance imaging

RR – relative risk

PTH – parathyroid hormone

РКИ – randomized controlled trial

DM – diabetes mellitus

GFR – glomerular filtration rate

ESR – erythrocyte sedimentation rate

FLS – fracture liaison service

TBS – trabecular bone score

PE – pulmonary embolism

BMC – bone mineral content

BUA – broadband ultrasound attenuation

CTX – C-terminal telopeptide of type 1 collagen

DXA – dual-energy X-ray absorptiometry

FRAX – algorithm for assessing the individual 10-year probability of fractures

ISCD – International Society for Clinical Densitometry

P1NP – N-terminal propeptide of type 1 procollagen

QUS – quantitative ultrasound densitometry

RANKL – receptor activator of nuclear factor kappa-B ligand

SD – standard deviation

SOS – speed of sound

WHI – The Women's Health Initiative (name of the study)

Terms and Definitions

Secondary osteoporosis is osteoporosis that develops as a consequence of severe concomitant somatic pathology (including endocrine disorders) or medication use [1–3].

Minimal trauma is a fall from standing height or lower onto the same surface, or even lesser trauma [4].

Pathological, low-traumatic (low-energy), or osteoporotic fracture is a fracture resulting from minimal trauma, in the vast majority of cases due to osteoporosis. The term pathological fracture is also used to describe a fracture due to disease rather than traumatic impact, for example, a fracture in patients with skeletal metastases, Paget's disease, etc. An osteoporosis-related fracture can be classified as a pathological fracture, and this term is used in the 10th and 11th revisions of the ICD; therefore, for standardization purposes, the term "pathological fracture" will be used hereafter [5].

Primary osteoporosis is osteoporosis that develops as an independent disease [1, 2].

Severe osteoporosis is osteoporosis with a pre-existing pathological fracture of the vertebra(e), femoral fracture, or multiple fractures regardless of the degree of bone mineral density (BMD) reduction according to X-ray densitometry.

Osteoporosis complicated by a pathological fracture is osteoporosis complicated by a pathological fracture of any localization (excluding those fractures that fall under the definition of severe osteoporosis), excluding phalangeal and skull fractures, which are not a consequence of osteoporosis [3].

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Osteoporosis is a metabolic skeletal disease characterized by low bone mass, microarchitectural deterioration of bone tissue, and, consequently, fractures resulting from minimal trauma [5, 6].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Osteoporosis is a multi-etiological disease whose development depends on genetic predisposition, lifestyle, physical activity, endocrinological status, concomitant diseases, medication use, human aging, and individual life expectancy [1–3]. Bone mass accumulation occurs in childhood and adolescence, reaching its peak by 20–30 years of age. After reaching the peak, bone mass remains practically unchanged until 35–40 years of age, and then begins to gradually decrease. In women, the rate of BMD decline is significantly higher than in men, which is due to estrogen deficiency during the peri- and postmenopausal periods.

Bone tissue is in a state of constant remodeling. Two opposite processes occur simultaneously: bone formation and bone resorption, and bone mineral density (BMD), quality, and strength depend on the balance between them. Under conditions of estrogen deficiency, this balance shifts towards bone loss. However, estrogen deficiency is not the only cause of BMD loss, as previously believed. Bone remodeling depends on the state of mineral metabolism, parathyroid hormone (PTH), vitamin D, growth hormone, calcitonin, thyroid hormones, glucocorticoids, aging and the associated secretory phenotype, etc. In general, all effects on bone metabolism are mediated through the main regulatory systems of osteoblastogenesis (canonical Wnt signaling pathway) and osteoclastogenesis (RANKL/RANK/OPG). Changes in the expression of osteoblastogenesis and osteoclastogenesis regulatory molecules with age and due to the negative influence of other factors lead to a decrease in bone mass, disruption of internal microarchitecture, reduced BMD, and, consequently, fractures from minimal trauma [2]. Thus, pathological fractures associated with osteoporosis can occur from a fall from standing height, an awkward movement, coughing, sneezing, and even without any apparent trauma.

1.3 Epidemiology of the Disease or Condition

In Russia, among individuals aged 50 years and older, osteoporosis is detected in 34% of women and 27% of men, and the prevalence of osteopenia is 43% and 44%, respectively. The frequency of osteoporosis increases with age [7]. Overall, about 14 million people suffer from osteoporosis and another 20 million have reduced BMD corresponding to osteopenia [8]. Similar prevalence rates of osteoporosis in women have been reported among the white population of North America and a number of Western European countries [2, 3].

The social significance of osteoporosis is determined by its consequences—vertebral and peripheral skeletal fractures, leading to high healthcare costs and causing a high level of disability, including incapacity and mortality.

The most typical fractures due to osteoporosis are fractures of the proximal femur, radius, and vertebral bodies, but fractures of other major skeletal bones (pelvis, ribs, sternum, lower leg, humerus, etc.) are also common [9]. A cross-sectional epidemiological study among the urban population of Russia showed that 24% of women and 13% of men aged 50 and older had previously experienced at least one pathological fracture, with vertebral fractures being the most common [10]. The prevalence of pathological vertebral fractures is about 10% in men and 12.7% in women [8]. According to an epidemiological study conducted in 16 Russian cities (total population aged 50 and older was 1,749,274) in 1992–1997, the incidence of femoral neck fracture was 100.9 per 100,000 population, with fractures being significantly more common among women (115.5 per 100,000) compared to men (77.0 per 100,000), p <0.0001 [7]. The fracture rate was lowest in both sexes aged 50–54 years, increased smoothly up to age 65, and then showed an exponential rise in fracture incidence, particularly pronounced in women. Over the 5-year fracture registration period, an increase in femoral fracture rates was noted in both women and men [7]. A similar study was conducted 11 years later (2008–2009) in four Russian cities, which showed that the incidence of proximal femoral fractures was already 239 cases per 100,000 population (276 and 175 cases in women and men, respectively). Furthermore, in men aged 50–64 years, the fracture rate was twice as high as in women, whereas in those aged 75 and older, the diametrically opposite trend was observed [10].

Mortality rates during the first year after a hip fracture range from 12 to 40%, with this indicator being higher in men [9]. Mortality is especially high during the first 6 months after a fracture, exceeding by 5–20% that of individuals of the same age without fractures, and in some Russian cities, mortality was 8 times higher than citywide mortality rates for individuals of the same age [11]. Patients who have suffered pathological fractures experience a significant decline in quality of life, which is only partially restored on average after 12–24 months, depending on the fracture location [11]. Thus, among survivors of a hip fracture, every third person loses the ability to care for themselves and requires long-term continuous care. The recovery of quality of life in surviving patients who have suffered a proximal femur fracture takes an average of 2 years and depends on whether surgical treatment was performed.

Distal forearm fracture is one of the most common fractures resulting from a fall from standing height. According to an epidemiological study in Russia, its incidence was 426 per 100,000 population, exceeding the incidence of hip fracture by 3–7 times in men, 4–8 times in women, and significantly prevailing in women. Furthermore, over the five-year period, there was a significant increase in the incidence of fractures of any localization, especially in patients who had already suffered a fracture [7].

The average cost of 1 year of treatment for osteoporosis complicated by fracture was 61,151 rubles (2016), with the treatment of patients with proximal femur fractures being the most expensive, and distal forearm fractures being the least costly [12]. Taking into account epidemiological data on the incidence of pathological fractures, recalculation for the population of Russia aged 50 and older showed that direct medical costs alone for the treatment of pathological fractures of five major localization sites in one year can reach about 25 billion rubles; meanwhile, the costs of treating patients with vertebral body fractures, which occur in the population in approximately 10% of individuals aged 50 and older, are almost twice the cost of treating patients with femoral fractures nationwide [12].

A comparative study of the social and economic consequences of femoral neck fracture and myocardial infarction showed that with equal treatment costs for these two diseases, patients with a fracture have a significantly lower quality of life, caused primarily by the lack of surgical treatment or poor rehabilitation, and, as a consequence, chronic pain syndrome and motor disorders [13].

Taking into account the projected increase in life expectancy in Russia, an increase in cases of pathological fractures will be observed in the coming years. For example, by 2035, the number of proximal femur fracture cases will increase by 36% in men and by 43% in women [14].

Thus, the high and constantly growing prevalence of osteoporosis, the significant cost of treating both the disease itself and its direct complications – fractures, the development of pain syndrome, deformities, and the loss of working capacity and the ability for self-care determine the high importance of this problem for the healthcare system of the Russian Federation.

1.4 Features of Coding the Disease or Condition

M81.0 Postmenopausal osteoporosis

M81.1 Oophorectomy osteoporosis

M81.2 Disuse osteoporosis

M81.3 Postsurgical malabsorption osteoporosis

M81.4 Drug-induced osteoporosis

M81.5 Idiopathic osteoporosis

M81.8 Other osteoporosis

M81.9 Osteoporosis, unspecified

1.5 Classification of the disease or condition

Primary osteoporosis develops as an independent disease without an identified alternative cause of skeletal fragility, accounting for 95% of the structure of osteoporosis in postmenopausal women (postmenopausal osteoporosis) and 80% of the structure of osteoporosis in men over 50 years of age [1–3, 15]. Primary osteoporosis also includes idiopathic osteoporosis, which develops in premenopausal women and men under 50, and juvenile osteoporosis, which is diagnosed in children (under 18 years of age). Idiopathic and juvenile forms of primary osteoporosis are extremely rare.

Secondary osteoporosis develops as a result of various diseases or conditions, as well as the use of medications, meaning there is a specific underlying cause leading to osteoporosis (Table 1). In the structure of osteoporosis, secondary osteoporosis accounts for 5% in women and 20% in men [15].

Table 1. Conditions, diseases, and medications capable of causing secondary osteoporosis [1, 2, 15]

*Osteogenesis imperfecta, hyperparathyroidism, and hypophosphatasia are metabolic bone diseases predominantly affecting the skeletal system and therefore may be considered as independent nosological entities.

A mixed etiology of osteoporosis may develop. For example, in postmenopausal women receiving glucocorticoids due to a severe somatic condition that itself can lead to secondary osteoporosis. In such cases, it is very difficult to isolate the primary cause of decreased bone strength.

1.6 Clinical presentation of the disease or condition

Prior to the development of a pathologic fracture, osteoporosis is clinically silent. Unlike osteoporosis, an acute pathologic fracture often presents with prominent clinical manifestations. The fracture is associated with pain and functional impairment, and is diagnosed radiographically by an orthopedic trauma surgeon, who may suspect osteoporosis based on the nature of the preceding trauma.

Of particular note are the clinical manifestations of vertebral body pathologic fractures, which may remain undiagnosed for a long time. Vertebral compression fractures are accompanied by back pain or fatigue, loss of height, and—in the case of multiple compression deformities—a wide range of clinical manifestations presented in Figure 1.

Figure 1. Clinical manifestations of multiple vertebral body compression deformities

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria for osteoporosis:

1) History or radiographic detection of pathologic fractures of major skeletal bones (femur, vertebral body/bodies, multiple fractures) regardless of dual-energy X-ray absorptiometry (DXA) or FRAX results (provided other skeletal disorders are excluded).*

2) High individual 10-year probability of major osteoporotic fractures (FRAX score meets or exceeds the Russian intervention threshold) regardless of bone mineral density (BMD) measurement by DXA.

3) BMD T-score of -2.5 standard deviations (SD) or lower at the femoral neck, total proximal femur, and/or lumbar spine (L1-L4, L2-L4) measured by DXA in postmenopausal women and men aged 50 years and older.

* if a pathologic fracture is identified, code as M80.0

2.1 Complaints and Anamnesis

Prior to the development of a pathologic fracture, osteoporosis is asymptomatic. Therefore, during history-taking, it is essential to first evaluate the individual 10-year probability of a pathologic fracture using the FRAX (fracture risk assessment tool) algorithm.

• Screening to identify high fracture probability groups is recommended using the FRAX algorithm among all postmenopausal women and men over 50 years of age [14, 16–23].

LoR ALoE 1Level of Recommendation A (Level of Evidence – 1)

Comments:

Given the high prevalence of osteoporosis and pathologic fractures in older age groups [1–3], their severe disabling consequences, and high treatment and rehabilitation costs [8–12], screening to identify patients at high risk of fractures among individuals over 50 years of age is justified. The effectiveness of the FRAX algorithm has been confirmed by a randomized controlled trial demonstrating a reduction in hip fracture rates with active screening compared to conventional follow-up [16].

Risk factors for major osteoporotic fractures and hip fracture included in the FRAX algorithm were identified from 12 prospective cohort studies across multiple geographic regions using primary databases [5, 24]. Each risk factor included in FRAX increases fracture probability independently of BMD, but can be combined with BMD measurement in an individual patient [3, 5, 24]. Key factors are summarized in Appendix G1.

Currently, there are no randomized trials evaluating screening tools in men. However, fracture risk and treatment of osteoporosis in men are determined in the same manner as in women, based on studies confirming efficacy using surrogate endpoints. Validation of the algorithm in men has been confirmed in large prospective cohort studies (CaMos [20], Manitoba [21], UK [18], Norway [19]), where predicted and actual fracture rates were comparable. FRAX calibration takes into account fracture and mortality data for both sexes, ensuring the universal applicability of the algorithm. In Russia, it has been proposed to use a fixed intervention threshold for men [25], but data supporting this approach are limited and inferior in evidentiary strength to large observational studies.

During the FRAX-based interview, along with other risk factors, the physician inquires about a history of fractures. If the answer is positive, it is necessary to clarify the localization of the fracture and the nature of the trauma [5].

• In the presence of a history of pathologic fractures of major skeletal bones (femur, vertebral body/bodies, multiple fractures), it is recommended to establish a diagnosis of osteoporosis (ICD code M80) and prescribe treatment in accordance with the Clinical Guidelines on Pathologic Fractures Complicating Osteoporosis, regardless of lumbar spine and proximal femur DXA or FRAX results (provided other skeletal disorders are excluded) [5, 26–37].

GCR BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: If a pathologic fracture is detected, it is coded as M80, and diagnosis and treatment are carried out in accordance with the Clinical Guidelines on Pathologic Fractures Complicating Osteoporosis. A pathologic fracture is a key complication of osteoporosis, which combines decreased bone mass and impaired microarchitecture, whereas densitometry reflects only reduced BMD and serves as a risk factor for fractures. Regardless of BMD, age, and other clinical risk factors, radiographically confirmed vertebral fractures (even if completely asymptomatic), hip fractures, and fractures of other major skeletal bones are indicative of altered bone structure and decreased bone strength, and represent significant predictors of new vertebral and other skeletal fractures [3, 8, 26–28], therefore, the presence of a fracture following minimal trauma is sufficient to establish the diagnosis of "osteoporosis" and prescribe treatment in international clinical guidelines on osteoporosis [2, 3, 5]. In many studies, the prescription of anti-osteoporotic medications was based on the presence of a fracture. Numerous studies, including meta-analyses, have shown that antifracture efficacy in individuals with prior fractures does not depend on baseline BMD [29–34]. However, a necessary condition for establishing the diagnosis of "osteoporosis" is the exclusion of other metabolic bone diseases [2].

2.2 Physical Examination

• All patients (postmenopausal women and men aged 50 years and older) are recommended to undergo a physical examination, including height measurement, assessment of chest shape and posture, and evaluation for skin folds on the upper back to detect clinical signs of vertebral compression fractures [1–3].

GGR CLeE 5Grade of Recommendation C (Level of Evidence – 5)

Comments: When recording height measurements, it is necessary to clarify the maximum height in early adulthood (age 25) and/or at the last previous height measurement. A height loss of 2 cm or more over 1–3 years or 4 cm or more over a lifetime should raise suspicion of vertebral compression fracture(s).

The presence of skin folds on the back and flanks ("excess skin" sign), and a reduction in the distance between the costal margins and iliac crests to less than 2 finger widths are physical signs of vertebral compression fractures. These physical signs do not differ between men and women.

When measuring height, attention should be paid to the inability to stand fully erect and the appearance of a distance between the wall and the occiput, which is a symptom of vertebral compression fractures.

The characteristic kyphotic chest deformity, relative increase in abdominal volume ("protrusion" of the anterior abdominal wall), relative elongation of the limbs, and shortening of the trunk are shown in Figure 1 and are symptoms of multiple vertebral body compression deformities.

In addition, during physical examination, attention should be paid to the presence of symptoms of diseases leading to secondary osteoporosis (Table 1), which are quite specific to each pathology.

2.3 Laboratory Diagnostics

• A general (clinical) blood test is recommended for all patients with a newly established diagnosis of osteoporosis, as well as in cases of previously prescribed therapy failure, for differential diagnosis with other causes of increased skeletal fragility [38–42].

GGR CLeE 5Grade of Recommendation C (Level of Evidence – 5)

Comments: In primary osteoporosis, the general (clinical) blood test shows no specific changes. The detection of anemia and an elevated ESR makes it possible to suspect other diseases leading to reduced skeletal strength or the cause of secondary osteoporosis (Table 1 and Appendix A3.2).

Comments: Bone remodeling occurs throughout a person's life to adapt bone tissue, repair damage, and maintain mineral homeostasis. The main biochemical markers of bone remodeling that are most justified to determine in clinical practice are summarized in Table 2.

Table 2. Biochemical markers of bone remodeling

Note: *The N-terminal propeptide of type I procollagen and C-terminal telopeptide of type I collagen are considered the most stable, have good reproducibility, and are recommended for measurement in the majority of patients [48–50].

Up to 50% of treatment failure cases are due to poor patient adherence, including non-compliance with the regimen for oral bisphosphonates (BPs) or daily teriparatide injections**. A decrease in bone resorption markers during BP therapy correlated with BMD gains and, in a number of cases, independently determined a reduced fracture risk [52–56]. Additionally, an increase in P1NP in response to teriparatide therapy** is a predictor of BMD gains [57]. Assessing markers during therapy makes it possible to monitor treatment adherence. A meta-analysis showed a 46% reduction in fracture risk in patients with good compliance compared to those who did not fully follow the physician's recommendation [58]. It is recommended to determine baseline marker levels and repeat the measurement after 3 months, expecting at least a 30% change [59]. An inadequate response of bone turnover markers is an early signal indicating the need for additional patient education or a change in therapy. When dual-energy X-ray absorptiometry (DXA) of the lumbar spine and proximal femur is unavailable, bone turnover markers can serve as a surrogate criterion for treatment efficacy. Given biological variability, it is optimal to measure them at the same time of day and using the same analyzer [60]. It should be noted that bone turnover markers, including bone formation markers, increase following a fracture and this elevation may persist for up to 5 months, while no further increase may be observed during therapy with an anabolic agent.

• Measurement of serum C-terminal telopeptide of type 1 collagen and/or serum N-terminal propeptide of type 1 procollagen (P1NP) levels in the upper quartile of the reference interval is recommended to be evaluated as an additional risk factor for initiating osteoporosis therapy in postmenopausal women with osteopenia [50, 61–66].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: There is compelling evidence that high bone turnover marker levels predict more rapid bone loss [61–64, 67], although there is no established intervention threshold for an individual patient. A pharmacoeconomic study using a Markov model showed that treatment with alendronic acid** in women with osteopenia and bone turnover marker levels in the upper quartile of the reference interval is cost-effective [66]. Some specialists consider it reasonable to use markers to monitor the patient's status after treatment cessation. Although follow-up of patients after discontinuation of alendronic acid**, another weekly bisphosphonate, and zoledronic acid** revealed no correlation between an increase in turnover markers and an increased fracture risk [68–70], monitoring bone turnover markers after therapy discontinuation provides insight into the presence of the therapeutic agent in bone tissue and its mechanism of action. It should be noted that none of the drug discontinuation studies had sufficient statistical power to detect a relationship between elevated bone turnover markers and fracture risk.

Comments: To date, there is no well-established intervention threshold for a single laboratory assay and/or a single bone turnover marker to determine fracture risk in postmenopausal women, although it is known that bone turnover marker levels increase postmenopausally, reflecting bone loss [61–65].  Study results have revealed no correlation between baseline bone turnover marker levels and the efficacy of alendronic acid** in preventing fractures or increasing BMD [71]. Treatment efficacy is not determined by baseline marker levels [71, 72]. For example, in glucocorticoid-induced osteoporosis (GIO), despite a decrease in bone formation markers, BP treatment is effective in preventing fractures; in postmenopausal osteoporosis, especially after a fracture, marker levels may be elevated, yet teriparatide** remains effective in preventing new fractures. Thus, bone metabolism markers are only an additional risk factor when making treatment decisions and cannot influence the choice of therapy based on its mechanism of action. Practitioners are not recommended to establish a primary diagnosis of osteoporosis based on any laboratory tests alone [2, 3]. Primary osteoporosis is diagnosed solely on the basis of a fragility fracture, low BMD, or a combination of risk factors [2, 3, 5]. Laboratory tests are used to rule out other metabolic bone diseases that lead to the symptom complex of increased skeletal fragility and bone loss, meaning laboratory tests are performed for differential diagnosis. If the initial test results are normal, more detailed investigation is generally not required, and repeat diagnostic workup is performed if new symptoms appear or treatment fails.

2.4 Instrumental Diagnostics

The presence of a single vertebral compression fracture increases the risk of subsequent vertebral fractures by 3–5 times, and the risk of hip and other non-vertebral fractures by 2–3 times [29].

- with back pain [75, 76];

LoR CLeD 4Level of Evidence C (Level of Dermination of Evidence — 4) — for women

LoR BLeD 3Level of Evidence B (Level of Dermination of Evidence — 3) — for men

- patients with long-standing poorly controlled type 2 diabetes mellitus (DM) or those on insulin therapy [77];

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

- height loss of 4 cm or more during a lifetime or 2 cm or more documented during regular medical follow-up [78, 79];

- patients taking glucocorticoids [80];

- with diagnosed fractures of other localization [29, 81].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Vertebral body compression fractures may occur without severe pain. Furthermore, the clinical manifestations of a fracture are non-specific and may be attributed to another cause of back pain. At the same time, up to 20% of patients who have experienced a fragility vertebral fracture will sustain a second fracture within the following year [71, 72]. Therefore, active screening for vertebral body compression fractures is necessary, with referral for examination of patients who have a high probability of having a fracture. The clinical symptoms of vertebral body compression fractures are described in the physical examination section. Glucocorticoid use for more than 3 months and long-term uncompensated type 2 diabetes mellitus are the most significant risk factors for the development of vertebral body compression fractures [37, 77, 82]; therefore, patients with the aforementioned conditions should be actively evaluated. After the initial study, follow-up monitoring should be performed only in cases of documented prospective height loss, or if back pain or postural changes occur/recur [37, 83–86]. Repeat spinal X-ray is also advisable in patients when deciding to discontinue osteoporosis pharmacotherapy, since stopping treatment is undesirable in patients with acute vertebral body fractures.

Affected vertebrae often alternate with mildly affected or unaffected vertebrae («accordion» sign) or are located among vertebral bodies with similar linear dimensions of their anterior edges («smash» sign) [1, 87]. Primary osteoporosis never exhibits destructive changes, intraosseous sclerosis, cortical interruptions, vertebral body enlargement, or marked narrowing of the intervertebral discs. In individual cases, a single examination cannot accurately assess a particular deformity, which requires patient follow-up or a more detailed study of the fracture area using computed tomography (CT) or magnetic resonance imaging (MRI) [88, 89].

As an alternative to X-ray imaging, initial computed tomography or magnetic resonance imaging of the Th4–L5 spine with targeted analysis of vertebral body heights may be performed. In addition, if software is available, X-ray morphometry can be performed during bone densitometry for the initial assessment of the presence of pathological vertebral body fractures.

• As part of the primary screening for vertebral body compression fractures, it is recommended to use artificial intelligence-enabled software (AI software) for morphometric analysis of vertebral bodies during routine computed tomography scans performed for other indications [90–93].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: Russian AI-enabled software based on convolutional neural networks (CNNs) allows for automated vertebral body morphometry, determination of the ventral, middle, and dorsal dimensions of vertebral bodies from chest CT data, and calculation of the deformity index according to H. Genant's classification. The threshold for a significant vertebral body deformity index was set at ≥25% (Genant grades 2–3). Additionally, AI-enabled software can determine the X-ray density of vertebral bodies in Hounsfield units, and after asynchronous calibration of CT scanners, assess bone mineral density (BMD) in mg/ml, which currently has no diagnostic value, but extremely low values can be a reason for referral for X-ray absorptiometry. Opportunistically, 1,918 chest CT scans of patients over 50 years of age were analyzed. The final analysis included 1,888 patients (61.2% female). An independent expert analysis of all 1,888 patients was performed (consensus of three radiologists); compression fractures were identified taking into account: the semiquantitative method [87]; the ABQ method [94]; and the 2008 IOF recommendations. According to the AI, a compression deformity of ≥25% was detected in 17.9% of patients, whereas experts identified fractures in 5.4%. The diagnostic accuracy of the algorithm for detecting deformations of ≥25% was ROC-AUC 0.986; sensitivity 98.1%; specificity 86.9%. For deformations of ≥40%, sensitivity decreased (51.4%), but specificity was high (99.6%). A deformation of ≥31% was considered the optimal threshold (ROC-AUC 0.977; sensitivity 83.7%; specificity 98.0%). A retrospective analysis of the reports and conclusions of the patients included in the study revealed that compression fractures were correctly described by radiologists in only 20.6% of cases. Thus, the AI morphometric algorithm is an effective tool for opportunistic detection of compression deformities and vertebral body fractures in patients over 50 years of age [90].

Rules for performing standard radiography

Standard X-ray equipment is used for radiography. Obtaining lateral radiographs of the thoracic (Th4–Th12) and lumbar (L1–L5) spine requires compliance with a number of rules [87, 95]:

- the patient is positioned on their left side;

- mandatory correction of scoliotic spinal curvature using special foam wedges so that the line drawn along the spinous processes runs parallel to the table;

- use of a special breathing technique when performing thoracic spine radiography; the lumbar spine radiograph is taken during a breath-hold;

- it is advisable to use X-ray cassettes with special equalization screens for spinal radiography.

Methods for assessing vertebral body fractures.

A vertebral body compression fracture is a reduction in vertebral body height (compression deformity) in the anterior, middle, or posterior regions by 20% or more compared to other regions of the same vertebra [86].

The classification of grade 1, 2, and 3 fractures is shown schematically in Appendix A3.3.

Evaluation of vertebral body compression deformities, with subsequent classification of the severity of low-energy fractures, is possible by applying the semiquantitative method (Appendix A3.3) [87] and morphometric analysis based on lateral radiography results and morphometry during bone densitometry, CT, and MRI [94, 96, 97].

Practitioners are not recommended to diagnose osteoporosis based on indirect signs of increased skeletal bone radiolucency on standard radiographs in patients without vertebral body compression fractures. In some cases, the radiologist's report indicates signs of osteoporosis on radiography of various skeletal sites. Increased radiolucency of bone tissue is non-specific and largely depends on technical imaging conditions and film processing quality [1]. In the absence of characteristic vertebral body compression deformities (compression fractures), diagnosing osteoporosis based on radiographic data is unjustified [1]. CT, MRI, and skeletal scintigraphy may be considered as additional methods for differential diagnosis [88, 98–101].

Comments: If evaluation of complaints, medical history, physical examination, and spinal radiography reveals no fragility fractures, the decision on the need for osteoporosis therapy is made based on the 10-year probability of a fragility fracture [3].

The FRAX algorithm calculates the individual probability of hip fracture and major fragility fractures (clinically significant fractures of the vertebrae, hip, humerus, and forearm) [3, 5, 15, 105], also taking mortality risk into account [5]. Since fracture epidemiology and mortality vary across countries [106], FRAX is calibrated for regions with known statistics [107–110]. The intervention threshold based on Russian data [14], the lower intervention threshold, and the upper intervention threshold are summarized in Table 3 (reference materials).

The intervention threshold was proposed by the Russian Association on Osteoporosis (RAOP) based on statistical data obtained from trauma clinics in the cities of Yaroslavl and Pervouralsk [14, 111], and was subsequently refined by proposing lower and upper limits for the intervention threshold (Figure 2). It should be noted that both the epidemiological studies underlying the development of FRAX and the prospective cohort data used to evaluate the Russian intervention threshold [112] lack sufficient statistical power comparable to that of the United Kingdom or European countries with country-level epidemiological studies [3]. In this regard, individuals for whom dual-energy X-ray absorptiometry of the lumbar spine and proximal femur was recommended based on FRAX results (orange zone) and who are diagnosed with osteoporosis according to WHO criteria (T-score ≤ -2.5) should be recommended osteoporosis treatment without reassessing FRAX. The intervention threshold is applied equally to men and women. Several Russian studies have shown that an extremely low proportion of men reach the intervention threshold; therefore, experts proposed establishing a fixed intervention threshold of 10% for major osteoporotic fractures to initiate osteoporosis therapy in men [25]. However, these studies do not take into account the need to prescribe therapy to male patients with existing pathological vertebral fractures, hip fractures, and multiple fractures, as well as those diagnosed via osteodensitometry. When these patient cohorts are excluded, the proportion of men requiring osteoporosis treatment may be significantly lower. Currently, there is insufficient evidence to alter the intervention threshold for men and make it different from that for women.

Limitations of FRAX

It must be taken into account that FRAX is not indicated for use in young adults and children. The FRAX tool has not been validated in patients who have previously received or are currently receiving pharmacotherapy for osteoporosis. However, patients who discontinued medications 2 or more years ago may be considered untreated [113]. FRAX can be calculated by including BMD / T-score at the femoral neck and does not account for lumbar spine BMD. The WHO determined that for many secondary causes of osteoporosis, fracture risk is primarily driven by the underlying disease's impact on BMD [24]. For this reason, when femoral neck BMD is included in the online FRAX calculation, the indicated values for "secondary causes of osteoporosis" are automatically set to zero. The algorithm for assessing 10-year fracture probability has limitations that require clinical judgment. Thus, if a patient has multiple fractures, the subsequent fracture risk will be underestimated by the FRAX tool. Such patients are prescribed osteoporosis treatment regardless of their FRAX score. FRAX does not account for glucocorticoid dose, cigarette smoking, or alcohol consumption, nor does it account for the impact of type 2 diabetes mellitus on fracture risk.

Comment: The conversion of individual 10-year fracture probability according to glucocorticoid dose is summarized in Table 4 [3].

Table 4. Average adjustment of 10-year probability of hip fracture and major osteoporotic fractures in postmenopausal women and men according to glucocorticoid dose [3]

• When assessing the individual 10-year probability of fractures (FRAX) in individuals with type 2 diabetes mellitus, it is recommended to adjust the obtained result by adding the additional risk associated with rheumatoid arthritis (set this risk factor to "yes"), and also to enter the trabecular bone score (TBS) results if available [117–119].

GGR CLeE 5Grade of Recommendation C (Level of Evidence – 5)

Comment: Based on a retrospective study in the province of Manitoba and the position of the International Osteoporosis Foundation's Diabetes Working Group, amendments for FRAX application are proposed: in patients with type 2 diabetes mellitus, it is recommended to check "yes" for rheumatoid arthritis and to enter the TBS value, which reflects bone quality deterioration in diabetes better than BMD [117, 118]. Other possibilities for improving FRAX sensitivity to identify high-risk fracture populations among patients with type 2 diabetes mellitus were also considered, specifically decreasing the femoral neck T-score by 0.5 standard deviations when entering osteodensitometry data and increasing the patient's age by 10 years. However, it was decided primarily to use the addition of an extra risk comparable to rheumatoid arthritis or a surrogate marker of bone quality [119].

• Dual-energy X-ray absorptiometry (DXA) of the lumbar spine and proximal femur is recommended for individuals with an individual 10-year probability of major osteoporotic fractures (FRAX) falling between the low and high fracture probability thresholds (Table 3 or the orange zone in Figure 2) for the diagnosis of osteoporosis [105, 120–125].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: X-ray absorptiometry of the proximal femur and lumbar spine can be used for the following purposes:

1. To establish or confirm a diagnosis of osteoporosis according to the 1994 WHO recommendations (Table 5);

Table 5. Diagnosis of osteoporosis based on reduced BMD according to WHO criteria [5] for postmenopausal women and men aged 50 years and older

*Severe osteoporosis is currently defined as osteoporosis with a pathological hip fracture, vertebral fracture, or multiple fractures regardless of BMD reduction.

2. to predict/calculate fracture risk depending on the degree of BMD reduction;

3. to monitor the patient's condition dynamics with or without therapy.

Universal screening of all postmenopausal women using lumbar spine and proximal femur X-ray absorptiometry is economically unfeasible, as it exceeds the cost of treating all pathological fractures by 2–10 times; therefore, the only reasonable strategy is selective screening in risk groups [84]. Previously, there was a wide range of indications for axial skeleton X-ray absorptiometry. However, key fracture risk factors are now integrated into the FRAX algorithm and can be assessed via an online resource. Due to the insufficient number of osteodensitometers in the Russian Federation, lumbar spine and proximal femur X-ray absorptiometry is recommended for individuals with a moderate individual fracture probability (FRAX orange zone, Figure 2), i.e., when the prescription of treatment is uncertain. The use of BMD values in combination with clinical risk factors improves the prediction of hip fractures and pathological fractures in general in both women and men [101]. This sequential application of the FRAX algorithm and X-ray absorptiometry has been validated [24, 120, 122, 126], and the therapeutic intervention strategy has demonstrated cost-effectiveness [127, 128].

Comments: The main indicators of bone tissue mineralization during DXA examination are [131, 139–141]:

- Bone mineral content (BMC) – the amount of mineralized tissue (g) during bone scanning, determined by the length of the scanning path (g/cm);

- BMD (bone mineral density) – the amount of mineralized bone tissue in the scanned area (g/cm²) is estimated.

In modern clinical practice, individual BMD is compared with a reference database. Due to differences in BMD measurement methods depending on diagnostic equipment variations, the most acceptable method for assessing BMD is the use of T- and Z-scores [132].

- The T-score reflects the deviation above or below the mean value from the peak bone mass of young women aged 20–29 years and is used for postmenopausal women and men over 50 years of age. It forms the basis of the WHO classification (1994, updated in 2013) [134] (Table 5).

- The Z-score represents the standard deviation above or below the mean BMD value in healthy men and women of a similar age.

In premenopausal women, men under 50 years of age, and children, the diagnostic classification based on the T-score is not applied. In these groups, the diagnosis of osteoporosis should not be made solely on the basis of densitometric criteria. The International Society for Clinical Densitometry (ISCD) recommends using ethnic- and race-adjusted Z-scores instead of the T-score; values of -2.0 and below should be defined as "low BMD for chronological age" or "below the expected range for age", and values above -2.0 as "within the expected range for age" [139, 141].

X-ray densitometry indices served as the inclusion criteria in the vast majority of clinical trials on the efficacy of drugs for the treatment of osteoporosis, and it is in these populations that the anti-fracture efficacy of therapy against the background of improved BMD has been demonstrated; therefore, when a decrease in BMD corresponding to osteoporosis is detected, it is justified to recommend existing therapy.

• The trabecular bone score (TBS) result obtained during standard dual-energy X-ray absorptiometry of the lumbar spine is recommended to be used for simultaneous inclusion in the FRAX algorithm in patients undergoing screening for osteoporosis in order to increase the sensitivity of the method for identifying patients at high risk of fractures [142].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: According to meta-analysis results, TBS showed an independent contribution to fracture risk prediction and was introduced into the FRAX algorithm to increase the sensitivity of the method [118]. TBS is a tissue parameter that assesses pixel gray-level variations on densitometric images of the lumbar spine; in other words, it is an indirect indicator of trabecular microarchitecture [143]. Unlike DXA, there is no separate intervention threshold for this parameter. For postmenopausal women, a TBS gradation based on the degree of microarchitecture deterioration has been developed: degraded microarchitecture TBS ≤1.23; partially degraded microarchitecture >1.23 but <1.31; and normal microarchitecture ≥1.31 [134, 142–144]. However, this classification is used for research purposes and cannot yet serve as a basis for treatment.

Practitioners should not diagnose osteoporosis based on ultrasound densitometry data, measurement of BMD of the non-axial skeleton (e.g., BMD of the calcaneus, radius, etc.), nor use non-standard patient positioning methods not approved by the densitometer manufacturer (e.g., lateral decubitus X-ray densitometry) and other skeletal sites measured by X-ray densitometry (e.g., Ward's triangle). These methods are not validated compared to standard dual-energy X-ray absorptiometry and are characterized by high variability [144].

All calculations and fracture risk gradations are based on relative indicators: standard deviations from the reference database of young healthy women (peak bone mass). Reference data were obtained for specific skeletal sites using established patient positioning [113, 132, 140–142]. These norms are not reference standards for other skeletal sites and other positioning methods.

2.5 Other Procedures

Table 6 shows other diagnostic techniques that were technologically developed to assess fracture risk [145], but were not used as inclusion criteria in clinical trials of osteoporosis drugs. T-scores obtained using these technologies cannot be reliably used for diagnostic classification purposes, as they are not equivalent to T-scores obtained by DXA. More detailed information on these technologies is provided in the reference information Appendix A 3.5.

Although these technologies can be partially used in clinical practice (femoral neck T-score measured by QCT as an additional risk factor in the FRAX algorithm) and research, it is not recommended to refer patients for these examinations for the purpose of diagnosing osteoporosis, and/or decisions regarding the initiation of osteoporosis therapy should not be made based on these technologies [146–150].

Radiofrequency echographic multispectrometry (REMS) demonstrates the closest correlation with DXA. Equivalence studies between this technology and DXA have been conducted in Italy and several European centers. Based on the data obtained, we can speak of a surrogate correlation with DXA, and upon verification in the Russian population and analysis of the comparability of treatment response results, this technology can be used under certain conditions as an adjunct to DXA (when DXA is unavailable, in bedridden or immobile patients).

2.5.1 Specialist Consultations and Monitoring

Comment: the disease requires diagnosis and treatment by various specialists, especially severe and secondary osteoporosis. The multidisciplinary team may also include a medical rehabilitation specialist (medical rehabilitation physician / physical and rehabilitation medicine physician / exercise therapy physician / physical therapist), as well as physicians of other specialties. The frequency of consultations is determined individually taking into account the patient's age and disease severity.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

Osteoporosis medications can be conditionally divided into antiresorptive therapy (bisphosphonates [BPs], denosumab**), which predominantly suppress bone resorption by acting on osteoclasts, and anabolic agents (teriparatide**, romosozumab), which predominantly enhance bone formation [9]. Due to the coupling of bone turnover, a decrease in bone destruction is generally accompanied by a decrease in bone formation, and vice versa. The clinical efficacy of drug therapy for osteoporosis is evaluated by a reduction in the number of fractures and indirectly by a number of surrogate criteria, such as changes in bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) or changes in bone remodeling markers. The main effects of osteoporosis medications, categorized by populations with different risks of pathological fracture, are summarized in Appendix A3.1.

• BPs are recommended for the prevention of pathological fractures and increasing BMD in patients with postmenopausal osteoporosis (alendronic acid**, ibandronic acid, zoledronic acid**), osteoporosis in men (alendronic acid**, zoledronic acid**), and glucocorticoid-induced osteoporosis (GIO) (alendronic acid**, zoledronic acid**) [161–174].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: Detailed results of registration studies are summarized in Appendix A3.1. Alendronic acid** reduces the incidence of vertebral and femoral fractures over 3 years of treatment in patients with a prior vertebral fracture or in patients with osteoporosis (T-score ≤-2.5) at the hip [161, 162]. Alendronic acid** also increases BMD in osteoporosis in men and in GIO in women and men [163, 164]. Ibandronic acid reduces the incidence of vertebral body fractures over 3 years, but does not affect the risk of non-vertebral fractures in the primary analysis of the BONE study [168]. Other doses of ibandronic acid (150 mg once monthly and 3 mg once every 3 months intravenously) have confirmed similar efficacy [169, 170]. The efficacy of ibandronic acid in preventing non-vertebral fractures has been shown in a meta-analysis [171]. Ibandronic acid 150 mg once monthly was studied in GIO (n = 140; T-score >-2.0 [161, 175, 176]) and in men (n = 132; T-score ≤-2.0 at the femoral neck) [177] and was effective in increasing BMD and decreasing bone remodeling markers. However, these indications are not officially registered, and prescribing ibandronic acid for GIO and male osteoporosis is off-label. Zoledronic acid** reduces the incidence of vertebral body fractures (with a significant risk reduction already at 1 year of treatment), femoral fractures, and non-vertebral fractures over 3 years in patients with a prior vertebral fracture or decreased BMD at the hip consistent with osteoporosis [172]. The drug has demonstrated anti-fracture efficacy in the treatment of osteoporosis in men [173], as well as in increasing BMD in GIO [174].

• Zoledronic acid** at a dose of 5 mg once a year is additionally recommended following surgical treatment for a proximal femoral fragility fracture (at least two weeks post-surgery) to prevent new fractures and improve patient survival [178].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: Zoledronic acid** infusions administered at least two weeks after hip fracture surgery in men and women for 3 years demonstrated improved survival and a reduced risk of new fractures compared with placebo [178] .

• Zoledronic acid** at a dose of 5 mg intravenous infusion once every 24 months is recommended for the prevention of BMD loss in postmenopausal women with osteopenia, and #zoledronic acid** once every 18 months for the prevention of fractures in women over 65 years of age with osteopenia [179, 180].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: Zoledronic acid** demonstrated efficacy in increasing BMD in women with osteopenia when administered as a regimen of 1 infusion of 5 mg for 2 years of therapy [179]. Furthermore, a 6-year double-blind study involving 2,000 women over 65 years of age with osteopenia at the hip (Total Hip and Neck T-score from -1.0 SD to -2.5 SD) showed a reduction in the risk of vertebral body fractures (hazard ratio 0.63; 95% CI 0.50 to 0.79; P < 0.001) and non-vertebral fractures (hazard ratio 0.66; P = 0.001) in patients receiving #zoledronic acid** 5 mg intravenous infusion once every 18 months compared with placebo [180].

• Denosumab** 60 mg once every 6 months is recommended for the prevention of pathological fractures and increasing BMD in women with postmenopausal osteoporosis, in men at high risk for fractures, in glucocorticoid-induced osteoporosis, as well as for the prevention of BMD loss and fractures in men with prostate cancer receiving androgen deprivation therapy, and #denosumab is indicated for the prevention of fractures in the absence of bone metastases in women receiving aromatase inhibitor therapy for breast cancer [181–191].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comments: The efficacy of denosumab** according to randomized controlled trials is summarized in Appendix A3.1 (reduction in the risk of vertebral body fractures by 68%, hip fractures by 40%, and non-vertebral fractures by 20% compared with placebo) [181]. An additional benefit of the drug in preventing falls was found during the study: 175 (4.5%) in the treatment group compared with 219 (5.7%) in the placebo group, p = 0.02, and, consequently, a reduction in contusion cases: 1 in the treatment group (<1%) compared with 11 (0.3%) in the placebo group. An increase in BMD similar to that observed in women was seen in men with low bone mass (+8% at L1-L4 and +3.4% at the femoral neck over 2 years of treatment) [182, 183]. The study on the efficacy of denosumab** compared with weekly bisphosphonate in individuals with GIO included 795 men and women aged ≥18 years receiving ≥7.5 mg of prednisolone**. All included patients under 50 years of age already had a history of pathological fracture, and among those over 50 years of age, there were patients with a BMD T-score ≤-2.0 or a fracture regardless of BMD. Patients were randomized to receive denosumab** injections 60 mg once every 6 months or a weekly bisphosphonate. According to the treatment results over 24 months, denosumab** was superior to weekly bisphosphonate in increasing lumbar spine BMD and hip BMD across all measured sites (at 24 months lumbar spine: denosumab** +6.2% vs. weekly bisphosphonate +1.7%, p < 0.001; Total Hip: denosumab** +3.1% vs. weekly bisphosphonate 0.0%, p < 0.001) [184].

Denosumab** prevented new vertebral fractures in women receiving therapy for hormone-dependent breast cancer without skeletal metastases [185]. In addition, denosumab** was effective in preventing fractures in men receiving androgen deprivation therapy for prostate cancer for 36 months without skeletal bone metastases (RR 0.38 [95% CI 0.19-0.78] [186].

• Denosumab** 60 mg once every 6 months is additionally recommended for patients with osteoporosis with greater BMD loss in cortical bone (femoral neck, radius), patients with compromised renal function, and patients in whom BP treatment was ineffective or failed to achieve the desired BMD gain [191–199].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: Unlike BPs, the distribution of denosumab** in bone tissue does not depend on the bone remodeling activity at the time of drug administration, which makes it possible to achieve a comparable concentration of denosumab** in trabecular and cortical bone and the continuous presence of the drug in any area of bone blood supply [193, 200, 201]. In addition, the clearance of denosumab**, as a protein molecule, does not depend on renal function [200, 201]. Denosumab** was more effective in increasing BMD in head-to-head comparisons with all BPs [191, 193, 194] and effectively increased BMD when administered both after BPs [195] and after teriparatide** [196].

• Teriparatide** at a dose of 20 mcg once daily is recommended for the prevention of pathological fractures and BMD gain in postmenopausal women with vertebral compression fractures, for the treatment of osteoporosis in men, and for the treatment of glucocorticoid-induced osteoporosis [30, 200–205].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: The clinical efficacy of teriparatide** at a dose of 20 mcg once daily has been demonstrated in postmenopausal women with a history of pathological vertebral fractures, regardless of baseline BMD reduction, prior fractures, and age (Appendix A3) [30, 31, 202], in men with reduced BMD [203], including due to hypogonadism, and in patients with glucocorticoid-induced osteoporosis (GIO) [204]. The increase in BMD and changes in bone turnover in men (437 patients aged 30–85 years, mean T-score in the femoral neck -2.7 SD) were consistent with the increase in BMD and changes in bone metabolism markers in women, suggesting a similar effect of teriparatide** on reducing fracture risk in men [199]. The most rigorous study of teriparatide efficacy for the treatment of GIO was conducted with 428 women and men aged 22 to 89 years [200]. Patients were randomized to those receiving teriparatide** at a dose of 20 mcg (n=214) and alendronate sodium** 70 mg (n=214). Treatment with teriparatide** for 18 months proved more effective in preventing vertebral fractures compared with alendronate sodium** (0.6% new vertebral fractures in the teriparatide group** compared with 6.1% in the alendronate sodium group**, p=0.004). Greater BMD gains were registered with teriparatide** compared with alendronate sodium** (+7.2% teriparatide** vs +3.4% alendronate sodium** in vertebrae, p<0.001; +3.8% teriparatide** vs +2.4% alendronate sodium** total in the femur, p=0.005) [200]. The use of teriparatide** in GIO was prolonged for 3 years, demonstrating good efficacy and safety with longer-term use [205].

• Teriparatide** at a dose of 20 mcg once daily is recommended for use as first-line therapy in patients with severe osteoporosis, as well as in cases of failure of previous therapy [205–211].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: Teriparatide** was more effective in preventing vertebral fractures compared with weekly bisphosphonates in a randomized controlled trial in postmenopausal women with a history of two vertebral compression fractures [208]. After 24 months of treatment, new vertebral fractures occurred in 28 (5.4%) of 680 patients in the teriparatide group and in 64 (12.0%) of 680 patients in the weekly bisphosphonate group (hazard ratio 0.44, 95% CI 0.29–0.68; p < 0.0001). Clinical fractures occurred in 30 (4.8%) of 680 patients in the teriparatide group compared with 61 (9.8%) of 680 in the weekly bisphosphonate group (hazard ratio 0.48, 95% CI 0.32–0.74; p = 0.0009) [205]. Teriparatide** was also more effective than alendronate sodium** in preventing vertebral fractures in individuals with GIO [200]. Previously, superior efficacy of teriparatide** in increasing BMD and reducing back pain compared with other BPs was demonstrated [209–211].

In global clinical practice, teriparatide** is considered cost-effective primarily for individuals with severe osteoporosis (patients with pre-existing vertebral fractures, regardless of the degree of BMD reduction), in cases of failure or intolerance of other osteoporosis therapies, as well as for individuals at high risk of fractures who are intolerant to alternative therapy [2, 3]. In the Russian Federation, teriparatide** is included in the VGNLD and ONLS lists and is prescribed by a medical commission as an expensive 24-month treatment course.

• Romosozumab at a dose of 210 mg subcutaneously once a month for 12 months is recommended for postmenopausal women with osteoporosis and high fracture risk, as well as for postmenopausal women with severe osteoporosis* [212–216].

* In the presence of pathological fractures, it is coded as Osteoporosis with pathological fracture (M80) and treatment is carried out in accordance with and treatment is carried out in accordance with the clinical guidelines for pathological fractures complicating osteoporosis.

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comments: Romosozumab is a monoclonal antibody that binds to sclerostin, a key inhibitor of osteoblast differentiation (ATC M05BX Other drugs affecting bone structure and mineralization). Romosozumab enhances bone formation and reduces bone resorption. In the international randomized, double-blind, placebo-controlled FRAME (FRActure study in postmenopausal woMen with ostEoporosis) study, romosozumab 210 mg monthly reduced the risk of new vertebral fractures by 73% compared with placebo after 12 months of therapy. After transitioning to denosumab, the risk reduction at 24 months was 75%. BMD in the lumbar spine increased by 13.3%, and in the hip by 6.9% compared with placebo [210]. Another study, ARCH (Active-contRolled fraCture Study in postmenopausal women with osteoporosis at High risk of fracture), included 4,093 women with osteoporosis and high fracture risk. Romosozumab therapy provided a 37% relative reduction in the risk of vertebral fractures compared with alendronate sodium after one year of treatment. BMD gains were 13.7% in the lumbar spine and 6.2% in the hip versus 5.0% and 2.8% in the alendronate sodium group [211, 35].

In the ARCH and FRAME studies, the efficacy of romosozumab was also evaluated in patients with chronic kidney disease. In mild and moderate renal impairment (eGFR 30–89 mL/min/1.73 m²), the drug provided a statistically significant increase in BMD, while renal function remained stable over 12 months of therapy [217]. Data in end-stage renal disease are limited, but in a Japanese cohort of patients on hemodialysis, the BMD increase was 15.3% in the lumbar spine and 7.2% in the femoral neck, whereas no changes were observed in the untreated group [218].

In men, the efficacy and safety of romosozumab were evaluated in the BRIDGE study (245 patients). After 12 months of treatment, BMD gains were: spine +12.1% vs +1.2% (placebo), total hip +2.5% vs –0.5%, femoral neck +2.2% vs –0.2% (p < 0.001). However, the incidence of serious cardiovascular events was higher in the romosozumab group (4.9% vs 2.5%) [219, 215]. The indication for treating osteoporosis in men is not yet registered in the Russian Federation.

In the STRUCTURE study (436 women with postmenopausal osteoporosis after long-term bisphosphonate therapy), romosozumab was compared with teriparatide [220]. After 12 months, the BMD gain in the hip was +2.6% with romosozumab therapy versus a 0.6% decrease with teriparatide; in the lumbar spine, it was +9.8% and +5.4%, respectively (p < 0.0001). The incidence of serious adverse events was comparable in both groups.

Comments: In 2007, 2013–2014, restrictions on the use of strontium ranelate** were introduced by the European Medicines Agency due to new information regarding adverse events [221–223]. This drug is not recommended for patients with ischemic heart disease (IHD), cerebrovascular disease, peripheral artery disease, or poorly controlled hypertension, and must be discontinued if cardiovascular pathology develops, due to an increased risk of cardiovascular adverse events, in particular a 60% increase in the risk of myocardial infarction (RR 1.6; 95% CI 1.07–2.38). Strontium ranelate** is contraindicated in patients with thrombosis and thromboembolism, including a history thereof, as well as in patients with risk factors for thrombosis (constant or temporary immobilization). The use of strontium ranelate** is not recommended in patients over 80 years of age, as the risk of thrombosis and thromboembolism increases significantly in this age group.

Furthermore, rare but severe hypersensitivity skin reactions, in some cases fatal, have been associated with the use of strontium ranelate** [223].

According to the official position of regulatory authorities, the decision to prescribe strontium ranelate** can be made only in patients with severe osteoporosis when no other osteoporosis medication is suitable, taking into account all the restrictions listed above. If a decision is made to prescribe strontium ranelate**, it is necessary to monitor the risk of cardiovascular disease throughout the entire treatment period and discontinue the drug if symptoms of cardiovascular diseases, skin reactions, or the likelihood of thrombosis appear [221–224].

Duration of osteoporosis treatment. Sequential and combination therapy for osteoporosis

• For patients with osteoporosis without fragility fractures who achieve a therapeutic clinical effect (BMD up to -2.0 SD by T-score in the femoral neck (as well as L1–L4 and Total Hip) and no new fractures), it is recommended to discontinue BP therapy for 1–2 years followed by dynamic monitoring [225–227].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

Comments: A decrease in BMD to -2.5 SD by T-score is the traditional basis for initiating osteoporosis therapy, and this threshold remains applicable for resuming BP therapy or starting alternative therapy. Therapy may be resumed if a new major risk factor emerges [199]. According to recent systematic analysis data, it has been shown that as early as 1–2 years after BP discontinuation, the fracture rate begins to increase [228], which is why treatment holidays are approached with greater caution, particularly in the population of patients with a high risk of fractures and in patients with a history of prior fractures. If osteoporosis treatment was initiated due to reduced BMD in the lumbar spine without decreased BMD in the hip, it is justified to aim for a comparable T-score (-2.0 SD or better) in the lumbar spine. The duration of therapy in this case is not precisely defined, but the minimum treatment duration is 2 years, most commonly 3 years for intravenous BPs and 3–5 years for oral agents.

• For patients with severe osteoporosis, it is recommended to continue continuous long-term treatment for osteoporosis [46, 221, 227–232].

* In the presence of fragility fractures, it is coded as Osteoporosis with pathological fracture (M80), and treatment is carried out in accordance with the clinical guidelines for pathological fractures complicating osteoporosis.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: The average duration of continuous osteoporosis treatment with oral BPs to prevent fractures and increase BMD is 5 years, and with intravenous BPs, 3 years [225]. The maximum period of BP use in clinical trials is 10 years (alendronic acid**) [46]. The average and maximum treatment periods with BPs were determined based on a systematic review of evidence by the American Society for Bone and Mineral Research [221]. With denosumab** use [229], a sustained annual increase in BMD is maintained for 10 years across all skeletal sites, providing an advantage over BPs in terms of BMD gains, whereas with BPs, BMD increases in the femoral neck are observed only during the first 2–3 years [46, 222, 223]. However, there is no evidence of superior antifracture efficacy of denosumab** compared with BPs. Furthermore, there is no evidence regarding the necessity of discontinuing denosumab** therapy after 10 years of continuous use. During denosumab** treatment, no decrease in efficacy or increase in the risk of adverse events has been observed with increasing treatment duration; therefore, there is no rationale to discontinue treatment when clinically necessary [225]. With BP therapy, there is a risk of atypical fractures as the duration of therapy increases, especially after 8 years of use, but this risk decreases if BPs are discontinued even for 1 year.

• For patients with osteoporosis without a history of fractures, treatment with denosumab** is recommended until a BMD of -2.0 SD or higher by T-score is achieved in the femoral neck and lumbar spine; in all cases of denosumab** discontinuation, transition to BP therapy is required [200, 201, 230–237].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: A sustained annual increase in BMD across all skeletal sites and antifracture efficacy are maintained for 10 years of denosumab** use [225].

Upon discontinuation of denosumab** after 1–3 years of treatment, bone turnover markers and BMD return to baseline levels within 12 months, and recover again upon resumption of therapy [226, 227]. Data on the increased risk of fractures after denosumab** discontinuation are contradictory: both cases of multiple vertebral fractures and hypercalcemia have been described [234, 235, 238], as well as no increase in fracture incidence in observational studies [227]. There is reason to believe that prescribing BPs after long-term denosumab** use helps mitigate the adverse effects of discontinuation [232, 233]. According to systematic reviews and positions of international societies, the therapeutic effect of denosumab** is reversible because, unlike BPs, the drug does not accumulate in bone tissue [228, 229]. Since osteoporosis is a chronic disease, patients require either continuation of denosumab** therapy or a timely switch to alternative treatment.

Thus, given the superior efficacy of denosumab** for BMD gains compared to BPs in individuals with severe osteoporosis and pre-existing fractures, long-term denosumab** treatment for up to 10 years is justified [229], being both effective and safe. If osteoporosis therapy was prescribed solely based on low BMD, once the therapeutic effect is achieved (T-score of -2.0 SD or better), switching to BP therapy is possible due to the lack of a significant reduction in fracture risk with continued denosumab treatment. In this case, oral BPs can be recommended as early as 6 months after the last denosumab injection, whereas the administration of zoledronic acid** is justified approximately 8 months after the last denosumab injection [227].

• Following the completion of teriparatide** treatment, a transition is recommended to antiresorptive therapy with denosumab** for further BMD gains or BPs to preserve the therapeutic effect [193, 194, 196, 239–242].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: The maximum permitted duration of osteoporosis treatment with teriparatide** is 24 months. Upon completion of teriparatide** therapy, the administration of antiresorptive therapy is mandatory, as teriparatide** does not accumulate in bone tissue and its effects are reversible [1–3]. Combination therapy with teriparatide** and denosumab** can be considered in severe osteoporosis and significant bone loss, since denosumab** was the only antiresorptive agent shown to produce a more pronounced increase in BMD in combination with teriparatide** compared to teriparatide** monotherapy [235]. In a randomized trial, administration of denosumab** or BPs following teriparatide** demonstrated a more pronounced increase in BMD with denosumab** compared to BPs [236]; therefore, for individuals with insufficient BMD gains, further treatment with denosumab** until a therapeutic effect is achieved, followed by a switch to BPs, is justified. Administering teriparatide** after denosumab** is associated with BMD loss, and data on fractures are unknown [235]; consequently, in case of denosumab** failure, adding teriparatide** to the treatment regimen is more justified than replacing denosumab** with teriparatide**.

• Following the completion of romosozumab treatment, a transition is recommended to antiresorptive therapy with bisphosphonates (alendronic acid** or zoledronic acid**) or denosumab** to preserve the therapeutic effect [214–216, 243–248].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

In the FRAME study [214] denosumab** was administered after 12 months of romosozumab or placebo, and overall, after 24 months of such sequential therapy, the risk of fractures in the group of women who received denosumab** following romosozumab therapy was 75% lower than in the group of patients who received denosumab** after placebo (0.6% vs 2.5%, p<0.001). BMD in the lumbar spine and total hip increased by 13.3% and 6.9%, respectively, after 12 months of romosozumab treatment compared with placebo. The ARCH study also demonstrated the feasibility of transitioning from romosozumab to alendronic acid**. BMD in women treated with romosozumab followed by alendronic acid** increased by a total of 15.2% and 7.1% in the lumbar spine and total hip, respectively, over 2 years of treatment. At 24 months, the group of patients initially treated with romosozumab for 12 months followed by alendronic acid** showed a 48% reduction in the risk of vertebral fractures (RR 0.52; 95% CI 0.40–0.66), a 38% reduction in hip fractures, and a 19% reduction in non-vertebral fractures (RR 0.81; 95% CI 0.66–0.99) compared with alendronic acid** monotherapy. There are also data supporting the efficacy of intravenous zoledronic acid** administration following romosozumab therapy [243]. In the phase 2 study NCT00896532, a single intravenous infusion of zoledronic acid** following romosozumab therapy helped maintain BMD, whereas in patients who received no additional treatment, BMD in the spine and hip returned almost to or approached baseline levels prior to romosozumab treatment [243]. These findings confirm the importance of prescribing bisphosphonates or denosumab** after romosozumab treatment to maintain BMD and further reduce fracture risk [214, 215, 243, 244]. Following the transition from romosozumab to denosumab** or bisphosphonates, a further increase or maintenance of BMD was observed. In addition, anti-fracture efficacy is sustained for two years after switching from romosozumab to denosumab** or bisphosphonates [249].

• In case of ineffectiveness of ongoing osteoporosis therapy: development of 2 or more pathological fractures* during treatment; BMD loss of 4% at the hip and 5% at the spine across two consecutive measurements; or a change in bone turnover markers of less than 30% on treatment combined with BMD loss, it is recommended to reassess patient adherence to treatment, rule out secondary causes of osteoporosis and other metabolic bone diseases, and switch osteoporosis therapy [250].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: * If pathological fractures are present, they are coded as Osteoporosis with pathological fracture (M80), and subsequent management is carried out in accordance with the clinical guidelines for pathological fracture complicating osteoporosis

According to the developed consensus, therapy is switched in the event of failure of previous treatment: from oral to parenteral BPs and anabolic therapy [250]. At the same time, osteoporosis therapy can be prescribed in any sequence (except for replacing denosumab** with teriparatide**) at the physician's discretion and taking into account the patient's preferences regarding the dosing regimen. As previously recommended, in patients with newly diagnosed severe osteoporosis, it is most preferable to initiate treatment with anabolic therapy and then transition to antiresorptive therapy [208–211].

The choice of oral or parenteral forms of antiresorptive therapy, both for initial prescription and after anabolic therapy, is determined on an individual basis [1–3]. There is no reason to initiate osteoporosis treatment specifically with oral forms, but the preferential prescription of parenteral drugs is recommended for patients with upper gastrointestinal pathology. Denosumab** may have an additional advantage as first-line therapy in the presence of cortical bone BMD loss and impaired renal function. If secondary causes of osteoporosis, severe vitamin D deficiency, and low patient adherence are ruled out, switching the patient from oral BPs to parenteral ones and/or from antiresorptive therapy to teriparatide** anabolic therapy is justified [250]. In rare cases of extremely low BMD and severe osteoporosis, a combination of teriparatide** and denosumab** may be used by decision of a medical commission.

• All drugs for the treatment of osteoporosis are recommended to be prescribed in combination with Calcium carbonate + Colecalciferol, wherein the daily equivalent doses of calcium carbonate can range from 500–1000 mg of elemental calcium, and colecalciferol** 400–800 IU daily throughout the entire period of osteoporosis therapy [157–166, 168–170, 174, 177–180, 198–204].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: All drugs for osteoporosis therapy must be prescribed in combination with calcium supplements (500–1000 mg daily) and colecalciferol** (at least 800 IU daily), since proven efficacy based on RCT results has been demonstrated specifically for this combination [157–166, 168–170, 174, 177–180, 198–204]. There are small studies showing that instead of native vitamin D (colecalciferol**) in combination with BPs, alfacalcidol** can be used at a dose of 1 mcg, which achieves a positive effect even with a prior loss of up to 3% BMD when treated in combination with colecalciferol** [247, 248].

Data on the efficacy of drugs for the treatment of osteoporosis obtained from registration studies are detailed in Appendix A3.1 [162, 166, 177, 249, 250]. Indications, contraindications, and potential adverse events are documented in the product instructions. The risks of rare adverse events (atypical fractures, osteonecrosis of the jaw) during antiresorptive therapy are significantly outweighed by the potential benefits of treatment in patients at high risk of fracture [250].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Prevention of recurrent fractures and assessment of fall risk are mandatory components of the treatment program for elderly patients. Prevention of recurrent fractures involves treating the underlying disease, most commonly osteoporosis, which accompanies pathological fractures in elderly patients. The choice of drug for osteoporosis treatment following a pathological fracture is made individually from among registered medications. The prescription of antiresorptive therapy (BPs, denosumab**) does not affect the duration of fracture healing [255]. Experimental studies have noted that the administration of teriparatide** leads to a significant improvement in callus formation and positively affects fracture healing, but these data have not been officially confirmed in humans [255]. All medications are prescribed in combination with calcium and colecalciferol** supplements. In addition, attention must be paid to fall risk factors, and potentially modifiable fall risk factors should be eliminated. Fall risk factors are summarized in Table 7 [256].

Table 7. Fall risk factors [252]

In working with an elderly patient, it is necessary to address modifiable risk factors, such as correcting reduced visual acuity, reducing the intake of medications that impair concentration and negatively affect balance, and improving home safety (eliminating slippery floors, obstacles, poor lighting, and inconvenient or missing handrails) [255].

• Patients with osteoporosis-related back pain, pain occurring under axial load, and spinal static disorders (hyperkyphosis) are recommended the use of orthoses to reduce pain [256–264].

Level of Evidence 2Grade of Recommendation B (Level of Evidence – 2)

#If pathological fractures are present, they are coded as Osteoporosis with pathological fracture (M80)

Comments: Orthoses improve quality of life and posture and prevent an increase in the kyphosis angle [257, 258]. Wearing orthoses or posture correctors is recommended on a continuous or intermittent basis, with mandatory removal at night [259]. In cases of multiple fractures, thoracolumbar orthoses may be used [260]. Hyperextension braces may be worn according to individual indications [261, 262]. However, it should be understood that orthoses are not a treatment method for osteoporosis and are primarily needed to reduce pain and enable earlier mobilization of the patient. An orthosis should not be recommended if it does not relieve the patient's pain or increase physical activity [258, 259]. Prolonged wearing of braces can lead to muscle atrophy, so the use of braces for longer than 8–12 weeks is undesirable [260–262].

5. Prevention and Dispensary Observation

Osteoporosis prevention includes measures aimed at achieving peak bone mass in children and young adults, maintaining bone mass and preventing falls in healthy older individuals, and preventing falls and fractures in individuals with a history of fractures and osteoporosis.

Physical activity

• Weight-bearing physical exercises (walking, running, dancing, active games) are recommended for optimal peak bone mass accumulation in youth and maintenance of BMD in healthy elderly individuals (drawing up a physical therapy course plan; monitoring the effectiveness of physical therapy sessions) [265–267].

Leveled of Evidence CLevel of Data Reliability 2Level of evidence C (level of data reliability – 2)

Comments: Mechanical loading stimulates anabolic processes characterized by increased osteoblast activity and reduced bone resorption by osteoclasts [268]. When building peak bone mass, axial loads are justified, whereas in older age, a protective regimen is preferable, avoiding significant axial loads to prevent pathological vertebral body fractures.

Lack of physical activity, as well as excessive physical activity in adolescence, leads to lower peak bone mass accumulation [265]. Active children and young adults with higher muscle strength achieve a higher peak bone mass [265, 266].

• Moderate resistance training (pilates, tai chi, swimming, etc.) is recommended to strengthen the muscle corset, improve coordination, and enhance the quality of life in elderly patients with diagnosed osteoporosis (drawing up a physical therapy course plan; monitoring the effectiveness of physical therapy sessions) [269, 270].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Studies involving women with early menopause have shown that strength training resulted in small but significant changes in BMD [266]. A meta-analysis of 16 studies and 699 subjects showed a 2% improvement in lumbar spine BMD in the strength exercise group compared to the group without significant physical activity [271, 272].

Thus, in postmenopause, the beneficial effect of exercise on BMD is significantly less than in young individuals, but physical activity improves other important parameters, such as balance and muscle strength, which ultimately helps reduce the risk of falls and fractures [273–275].

Immobilization is a major cause of bone loss. Bedridden patients can lose more bone mass in a week than in a year of normal physical activity [276].

In elderly patients with severe kyphosis, back discomfort, and gait instability, the physical rehabilitation plan should focus on non-weight-bearing exercises, strengthening the back muscles, and balance training. The use of orthopedic devices may also be important. The most optimal approach is exercising under the supervision of an experienced physical therapy specialist.

To prevent falls, improve coordination, and strengthen muscles, strength training and other resistance exercises such as yoga, pilates, tai chi, and swimming can be included. Physiotherapy, such as electromyostimulation, can also be an important component of post-fracture rehabilitation [273]. These same measures should be considered for individuals with established osteoporosis and a high fracture risk, but without a prior fracture.

Vitamin D and calcium

Vitamin D is essential for intestinal calcium absorption and bone tissue mineralization. The main source of vitamin D in the body is its synthesis in the skin under the influence of ultraviolet radiation. Obtaining the required amount of this vitamin from food is difficult due to the limited number of foods that contain it in significant amounts [277, 278].

At the same time, studies show that lifestyle characteristics involving limited sun exposure and the use of active radiation protection (sunscreens) are major reasons for the high global prevalence of vitamin D deficiency in the population. Issues related to vitamin D are detailed in the relevant clinical guidelines [278].

• Treatment of vitamin D deficiency is recommended with cholecalciferol** when deficiency is established (serum 25(OH)D level ≤ 20 ng/ml), administered in therapeutic doses (optimally cholecalciferol 50,000 IU per week for up to 8 weeks), followed by a transition to maintenance therapy with cholecalciferol 800–4000 IU daily [278–285].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Comments: Long-standing low vitamin D levels can lead to suboptimal intestinal calcium absorption, resulting in secondary hyperparathyroidism with increased mobilization of calcium from bones, decreased BMD, and the development of osteoporosis, sometimes combined with osteomalacia. Vitamin D supports the formation and metabolic processes in muscle tissue, especially at the level of fast-twitch muscle fibers, which predisposes individuals with a deficiency of this vitamin to falls [286–288]. Serum 25(OH)D concentration is the best indicator for monitoring vitamin D status because it is the primary circulating form of vitamin D, has a long half-life of about 2–3 weeks, and reflects both dietary intake of vitamin D, intake of cholecalciferol** and ergocalciferol, and synthesis in the skin under ultraviolet exposure [287, 289].

Table 8. Interpretation of 25(OH)D concentrations adopted by the Russian Association of Endocrinologists [286]

Due to lower metabolic degradation of cholecalciferol (vitamin D₃), it is generally recognized as the drug of choice for correcting low vitamin D₃ levels[286].

Table 9. Treatment regimens for vitamin D deficiency and insufficiency

Doses to maintain a 25(OH)D level above 30 ng/ml in individuals with previously diagnosed low vitamin D levels are generally higher than preventive doses and amount to at least 1500–2000 IU of cholecalciferol** daily [280]. Due to evidence of an increased risk of falls with high doses of vitamin D in individuals over 65 years of age, for both vitamin D deficiency treatment and intermittent prevention, it is recommended to take no more than 50,000 IU of cholecalciferol at a time, especially in the older age group [290–292].

• Patients are recommended an adequate dietary intake of calcium (Table 10) or calcium supplements (carbonate) if dietary intake is insufficient [286, 293–295].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comments: Vitamin D is able to activate intestinal calcium absorption and skeletal mineralization only in the presence of adequate calcium intake itself. Antiresorptive therapy can dramatically increase the demand for calcium required for bone tissue restoration; therefore, alongside preliminary correction of vitamin D levels, ensuring adequate dietary calcium intake is crucial for the prevention and treatment of skeletal pathology [294].

During X-ray densitometry, the report calculates the BMC index, which reflects the calcium content in bone tissue. Inadequate calcium intake can contribute to impaired mineralization. The calcium content in food products is summarized in Appendix A3.4.

Recommended daily calcium intakes for various age groups are summarized in Table 10.

Table 10. Recommended daily calcium intake [284]

For the healthy population, calcium intake norms take into account all sources: dietary calcium and calcium supplements/preparations.

Calcium possesses a mild antiresorptive effect, potentiates the efficacy of mainstream osteoporosis medications, prevents hypocalcemia, and is recommended for any therapeutic regimens and protocols [295].

In some countries, commonly consumed foods (cereals, juices, bread) are fortified with calcium. This practice is not widespread in Russia. Adequate daily dietary calcium intake is considered to be the presence of at least three servings of dairy products per day in the diet. One serving can be considered as 30 g of cheese, 100 g of cottage cheese, 150 g of yogurt, 200 ml of milk [293]. The use of calcium dietary supplements is recommended in cases where the required calcium intake cannot be achieved through food products.

In a meta-analysis of 17 studies lasting up to three years, more than 50,000 patients received monotherapy with calcium supplements or in combination with cholecalciferol**. As a result of calcium alone, a 12% reduction in the risk of fractures at various sites, including the vertebrae, femur, and forearm, was observed (RR 0.88; 95% CI 0.8–0.95). The addition of cholecalciferol** did not lead to a significant reduction in fracture risk: with calcium alone, the risk decreased by 10%, and in combination with cholecalciferol**, by 13%. Notably, studies with good compliance (>80%) showed the greatest reduction in fracture risk, reaching 24% [273]. Another pooled analysis of 68,500 patients receiving cholecalciferol** alone showed no reduction in fracture risk. However, the combination of calcium supplements with cholecalciferol** reduced the risk of all fractures by 12% (p=0.025) and hip fractures by 26% (p=0.005) [280].

• Active vitamin D metabolites (alphacalcidol**, calcitriol**) are recommended in groups of patients with relative or absolute indications for their prescription (Table 11), and may also be recommended in elderly patients with a high risk of falls as monotherapy or in combination with antiresorptive therapy to improve BMD [296].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comments: Absolute and relative indications for prescribing active vitamin D metabolites are summarized in Table 11.

Table 11. Absolute and relative indications for prescribing active vitamin D metabolites [296]

Active vitamin D metabolites and their analogues have demonstrated greater efficacy compared to cholecalciferol** in reducing the risk of falls, especially in patients with reduced GFR [296]. At the same time, when 25(OH)D deficiency is established, correction of native vitamin D deficiency is a mandatory step in treatment and is performed, among others, in patients with end-stage renal disease [297], and diabetic nephropathy [298]. It must be remembered that active vitamin D metabolites and their analogues are not detected in significant amounts when measuring serum vitamin D concentrations due to their structural differences from cholecalciferol**, as well as their rapid degradation. Therefore, to monitor the effectiveness of prescribed doses of active vitamin D metabolites and their analogues, blood concentrations of total and/or ionized calcium and parathyroid hormone must be used. In addition, due to the potential risk of developing hypercalcemia/hypercalciuria, these drugs can only be prescribed under medical supervision of blood calcium levels and, in some cases, urine calcium levels (with a normal glomerular filtration rate). Active vitamin D metabolites and their analogues should also be used with caution when prescribed concomitantly with native vitamin D preparations containing a cholecalciferol** dose higher than the prophylactic one (more than 800–1000 IU per day) [286].

Menopausal hormone therapy (MHT)

MHT is approved for the prevention of postmenopausal osteoporosis, relief of vasomotor symptoms, and vulvovaginal atrophy associated with menopause [266]. Women who have not undergone hysterectomy require MHT containing progestogens for endometrial protection.

• MHT is recommended for the prevention of osteoporosis in women under the age of 60 with a postmenopausal duration of up to 10 years. It is recommended to use the lowest effective doses of MHT: as a woman's age increases, reduce the drug dose and perform an annual benefit-risk assessment in each specific case [299–302].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Comments: Evidence for fracture prevention with MHT is limited to data on the oral administration of standard doses of conjugated equine estrogens (CEE) and medroxyprogesterone**. The Women's Health Initiative (WHI) study revealed that MHT use for five years reduces the risk of vertebral and hip fractures by 34%, and non-vertebral fractures by 23% [299].

Although MHT prevents fractures at any age after the onset of menopause, the age at which MHT is initiated is important. At age 50–60, or within 10 years of menopause onset, the benefits of MHT most likely outweigh any risks, and MHT may be considered as first-line therapy. MHT should not be initiated after the age of 60. However, there are no mandatory restrictions on the duration of MHT use as long as it aligns with treatment goals [299, 301].

There is evidence regarding the prevention of BMD loss with oral (CEE) and transdermal use of doses lower than standard [302].

Adverse events associated with MHT use

The global Women's Health Initiative (WHI) study demonstrated an increased risk of CHD, stroke, invasive breast cancer, PE, and lower extremity deep vein thrombosis within 5 years of treatment with standard doses of CEE and medroxyprogesterone** [300]. However, subsequent re-analysis of these data did not confirm an increased risk of CHD in women under 60 years of age who initiated treatment within the first 10 years of postmenopause, while the increased risks of breast cancer, stroke, and thromboembolism persisted, though they were not as dramatic. The absolute risk of stroke and breast cancer in women under 60 was low. In the subgroup of women after hysterectomy receiving estrogen monotherapy under 60 years of age with a duration of menopause up to 10 years in the WHI, a reduction in the risk of breast cancer, CHD, and overall mortality was noted during 7 years of treatment [300]. Meta-analysis and observational data indicate a lower risk of thromboembolism and ischemic stroke with transdermal MHT [302].

Frequency of required examinations during dispensary monitoring

Because osteoporosis is classified as a chronic age-related disease, patients require lifelong monitoring.

• All patients (postmenopausal women and men over 50 years of age) are recommended to undergo an annual physical examination, including measurement of height, weight, assessment of chest shape and posture, and the presence of skin folds on the back of the spine to detect clinical signs of vertebral compression fractures [1–3].

GGR CLeE 5Grade of Recommendation C (Level of Evidence – 5)

Comments: When recording height measurements, it is necessary to check the result of the previous height measurement. If height has decreased by 2 cm or more since the previous measurement, vertebral body compression fracture(s) should be suspected.

The presence of skin folds on the back and flanks ("excess skin" sign), and a reduction in the distance between the costal margins and iliac crests to less than 2 finger widths are physical signs of vertebral compression fractures. These physical signs do not differ between men and women.

When measuring height, attention should be paid to the inability to stand fully erect and the appearance of a distance between the wall and the occiput, which is a symptom of vertebral compression fractures.

The characteristic kyphotic chest deformity, relative increase in abdominal volume ("protrusion" of the anterior abdominal wall), relative elongation of the limbs, and shortening of the trunk are shown in Figure 1 and are symptoms of multiple vertebral body compression deformities.

• Complete blood count (CBC) and blood biochemistry parameters including total calcium, albumin, creatinine (with estimated glomerular filtration rate (eGFR) calculation), inorganic phosphorus, alkaline phosphatase, and vitamin D are recommended to be assessed at least once a year, as well as in cases of previously prescribed therapy failure [2, 38–43].

GGR CLeE 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Laboratory test results help identify alternative causes of skeletal fragility and clarify contraindications to specific therapies (e.g., hypocalcemia is a contraindication to bisphosphonates (BPs) and denosumab**, while hypercalcemia and elevated alkaline phosphatase are contraindications to teriparatide**, etc.). Cohort studies have shown that up to 15–30% of patients may have other conditions leading to or aggravating osteoporosis [40–42]. Laboratory tests should be repeated if therapy is ineffective, due to the possibility of concomitant diseases or vitamin D deficiency as causes of inadequate treatment response [2, 43]. Detection of anemia and elevated ESR allows suspecting other diseases that lead to reduced skeletal strength or causes of secondary osteoporosis, as well as reasons for treatment failure.

Comments: Up to 50% of treatment failure cases are due to insufficient patient adherence, which includes not only refusing medication but also failing to follow the regimen and rules for taking oral bisphosphonates (BPs) or daily teriparatide** injections. A decrease in bone resorption markers in patients receiving BPs correlated with BMD gains and, in some cases, independently predicted a reduced fracture risk [52–56]. Furthermore, an increase in P1NP in response to teriparatide** therapy is a predictor of BMD gains [57]. Testing markers during therapy allows monitoring adherence to treatment. A meta-analysis of 171,063 patients followed for 1–2.5 years showed a 46% reduction in fracture risk in patients with good compliance compared to those who did not fully follow medical recommendations [58]. It is justified to test bone remodeling marker levels at baseline and then after 3 months of therapy, expecting at least a 30% change [59].

• Dual-energy X-ray absorptiometry (DXA) of the lumbar spine and proximal femur is recommended to evaluate the efficacy of ongoing therapy and the dynamics of BMD in patients with previously diagnosed osteoporosis and a treatment gap, with an interval of at least 12 months from the initial scan [51, 120, 129, 130].

AG RLEL 2Level of Evidence — 2 (Strength of Recommendation — B)

Comments: According to all conducted studies, dual-energy X-ray absorptiometry (DXA) is the most accurate method for monitoring therapy, having proven the correlation between on-treatment changes and reduced fracture risk when using approved osteoporosis medications; therefore, this method is used for follow-up, but no more frequently than once every 12 months [131].

• In patients with back pain, a height loss of 2 cm on regular medical monitoring, taking glucocorticoids, or with diagnosed fractures at other sites, thoracic and lumbar spine radiography (Th4-L5) in lateral projection is recommended [29, 75–81].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Vertebral body compression fractures can be painless or have mild pain. Moreover, clinical manifestations of a fracture are nonspecific and may be misattributed to other causes of back pain. At the same time, up to 20% of patients who experience a pathological vertebral body fracture will suffer a second fracture within the next year [71, 72]. Therefore, active detection of vertebral compression fractures with referral for imaging is necessary in patients with a high probability of a fracture.

As an alternative to X-ray imaging, initial computed tomography or magnetic resonance imaging of the Th4–L5 spine with targeted analysis of vertebral body heights may be performed. In addition, if software is available, X-ray morphometry can be performed during bone densitometry for the initial assessment of the presence of pathological vertebral body fractures.

6. Organization of Medical Care

Osteoporosis is a systemic chronic disease; therefore, management of such patients is generally carried out on an outpatient basis. However, in some cases, scheduled hospitalization is indicated for the differential diagnosis of osteoporosis and selection of therapy in severe cases with multiple fractures, the development of new pathological fractures during ongoing therapy, or the presence of bone pathology in young patients.

• To ensure timely initiation of osteoporosis therapy and long-term monitoring of patients aged 50 and older in order to reduce fracture risk, it is recommended to establish Fracture Liaison Services (FLS) [35, 36, 303–310].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: In the presence of pathological fractures, the code Osteoporosis with pathological fracture (M80) is used, and treatment is carried out in accordance with the clinical guidelines for pathological fractures complicating osteoporosis.

Following a low-energy fracture, the risk of subsequent fractures increases 2- to 3-fold [311, 312]. About 50% of proximal femur fractures occur in individuals who have previously sustained an osteoporotic fracture [312, 313]. At the same time, anti-osteoporotic treatment in routine practice is prescribed to less than 20% of patients [308, 314]. When such patients are monitored within an FLS framework, studies have shown a reduction in re-fracture rates by up to 40% [35, 36, 303, 315, 316], as well as a reduction in mortality [303, 304, 312, 315, 316] and high cost-effectiveness [305, 306].

To organize an efficiently functioning FLS, the following aspects must be considered: 1) Clinical and cost-effectiveness is demonstrated only if the FLS staff includes a dedicated nurse coordinator who ensures patient navigation [307]. 2) A system must be organized for systematic and active identification of all patients aged 50 and older with new low-energy fractures. 3) Patient evaluation (or referral for such evaluation to other medical institutions) must be organized to assess the risk of subsequent fractures in order to identify high-risk patients. For this, it is recommended to use the FRAX 10-year absolute fracture risk assessment and/or densitometry. Evaluation is also required to search for secondary causes of osteoporosis and assess fall risk. Since the risk of re-fracture is highest in the first months after the fracture, evaluation is recommended within the first 3 months. 4) Patient education is conducted to improve treatment adherence and reduce fall risk. 5) Following the assessments, medical and non-medical interventions should be applied, including fall prevention measures. It has been shown that prescribing pathogenetic treatment within 3 months after a fracture significantly reduces the rate of re-fractures and fracture-related surgeries compared to patients whose treatment was delayed [317]. 6) Long-term patient monitoring should be ensured within the FLS or through referral to primary care physicians or specialists. 7) Data on all patients identified in the FLS must be entered into a database. To optimize care delivery, the quality of FLS operations must be ensured, which includes data collection and monitoring.

Comments: In the presence of pathological fractures, the code Osteoporosis with pathological fracture (M80) is used, and treatment is carried out in accordance with the clinical guidelines for pathological fractures complicating osteoporosis.

Indications for planned hospitalization in a medical organization:

1) Presence of two or more vertebral body compression fractures;

2) Presence of one or more vertebral body compression fractures combined with a history of non-vertebral pathological fractures;

3) Presence of a pathological fracture in young patients (under 50 years of age).

Indications for patient discharge from a medical organization:

1) Determining the type of osteoporosis: primary or secondary;

2) Assessment of calcium-phosphorus metabolism, BMD, and exclusion of other fractures;

3) Selection of patient management tactics.

One of the complications of osteoporosis is a pathological femur fracture, which requires emergency hospitalization and surgical treatment by an orthopedic traumatologist within 48 hours, followed by patient mobilization.

Indications for emergency hospitalization to a medical organization:

1) Pathological femur fracture.

Indications for patient discharge from a medical organization:

1) Surgical treatment of the femur fracture;

2) Patient mobilization within the ward with the aid of a walker.

7. Additional Information

Patient adherence to pharmacotherapy has the greatest impact on the course and outcome of osteoporosis and the prevention of fractures. Medications for the treatment of osteoporosis reduce the risk of fractures only when taken regularly in combination with calcium supplements and vitamin D and its analogues. The duration and sequence of therapy, as well as continuity of care between surgical and medical specialists, are outlined in the section "Treatment, including drug and non-drug therapy, diet therapy, pain management, and medical indications and contraindications for treatment methods."

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Belaya, Z.E., MD, PhD, Professor, Head of the Department of Osteoporosis and Osteopathies, Endocrinology Research Centre of the Russian Ministry of Health, Moscow; Member of the Russian Association of Endocrinologists, Presidium Member of the Russian Association on Osteoporosis

2. Belova, K.Yu., MD, PhD, Head of the Regional Clinical and Diagnostic Center for Osteoporosis and Osteoarthritis, N.V. Solovyov Clinical Emergency Hospital; Associate Professor at the Department of Therapy named after Professor E.N. Dormidontov, Yaroslavl State Medical University; Member of the "Osteorus" Osteoporosis Patient Society, Presidium Member of the Russian Association on Osteoporosis, Member of the Association of Rheumatologists of Russia.

3. Biryukova, E.V., MD, PhD, Professor at the Department of Endocrinology and Diabetology, Faculty of General Medicine, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health; Member of the Russian Association of Endocrinologists

4. Gronskaya, S.A., Endocrinologist at the Department of Osteoporosis and Osteopathies, Endocrinology Research Centre of the Russian Ministry of Health, Moscow; Member of the Russian Association of Endocrinologists, Member of the Russian Association on Osteoporosis

5. Dedov, I.I., MD, PhD, Academician of the Russian Academy of Sciences, President of the Endocrinology Research Centre of the Russian Ministry of Health, Moscow; President of the Russian Association of Endocrinologists, Chief Freelance Specialist-Expert Endocrinologist of the Russian Ministry of Health

6. Dzeranova, L.K., MD, PhD, Chief Researcher at the Department of Neuroendocrinology, Endocrinology Research Centre of the Russian Ministry of Health, Moscow; Member of the Russian Association of Endocrinologists

7. Drapkina, O.M., MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Director of the National Medical Research Center for Preventive Medicine of the Russian Ministry of Health, President of the Russian Society for the Prevention of Noncommunicable Diseases, President of the S.P. Botkin National Society of Physician Enhancement, President of the Association of General Practice Physicians (Family Physicians) of Russia, President of the National Biobank Association

8. Dreval, A.V., MD, PhD, Professor, Head of the Department of Clinical Endocrinology, Faculty of Advanced Medical Training, Moscow Regional Research Clinical Institute (MONIKI) named after M.F. Vladimirsky, Head of the Department of Therapeutic Endocrinology at MONIKI, Chief Endocrinologist of Moscow Region

9. Dubovitskaya, T.A., Cand. Sci. (Med.), Endocrinologist, Endocrinology Research Centre of the Russian Ministry of Health, Moscow; not a member of a professional association

10. Dudinskaya, E.N., MD, PhD, Head of the Laboratory of Age-Related Metabolic and Endocrine Disorders, Russian Gerontology Clinical Research Center (a structural subdivision of the Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation); Member of the Russian Association of Endocrinologists, Member of the Russian Association on Osteoporosis

11. Ershova, O.B., MD, PhD, Professor at the Department of Therapy named after Professor E.N. Dormidontov, Yaroslavl State Medical University; Head of the "Osteorus" Osteoporosis Patient Society, Vice-President of the Russian Association on Osteoporosis, Member of the Association of Rheumatologists of Russia.

12. Zhdanova, A.S., Endocrinologist, Postgraduate Student at the Department of Osteoporosis and Osteopathies, Endocrinology Research Centre of the Russian Ministry of Health, Moscow; Member of the Russian Association on Osteoporosis

13. Kanis, J.A., International Consultant, Professor, Director of the Centre for Metabolic Bone Diseases, University of Sheffield, UK; Professor at the Australian Catholic University (Melbourne); Honorary President of the International Osteoporosis Foundation (IOF President from 2008 to 2017), Member of the IOF Committee of Scientific Advisors, Chair of the IOF Working Group on Epidemiology and Quality of Life

14. Kryukova, I.V., Cand. Sci. (Med.), Associate Professor at the Department of Endocrinology, M.F. Vladimirsky Moscow Regional Research Clinical Institute (MONIKI), Moscow; Member of the Russian Association of Endocrinologists

15. Lesnyak, O.M., MD, PhD, President of the Russian Association on Osteoporosis, Professor at the Department of Family Medicine, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, St. Petersburg; President of the Russian Association on Osteoporosis; Member of the Association of Rheumatologists of Russia

16. Mamedova, E.O., Cand. Sci. (Med.), Senior Researcher at the Department of Osteoporosis and Osteopathies, Endocrinology Research Centre of the Russian Ministry of Health, Moscow; not a member of a professional association

17. Marchenkova, L.A., Cand. Sci. (Med.), Leading Researcher, Head of the Department of Rehabilitation of Patients with Somatic Diseases, Head of the Division of Somatic Rehabilitation, Reproductive Health and Active Longevity, National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health; Presidium Member of the Russian Association on Osteoporosis, Member of the Russian Association of Endocrinologists

18. Melnichenko, G.A., MD, PhD, Academician of the Russian Academy of Sciences, Deputy Director for Research, Endocrinology Research Centre of the Russian Ministry of Health, Moscow; Chair of the Moscow Association of Endocrinologists, Vice-President of the Russian Association of Endocrinologists

19. Mokrysheva, N.G., MD, PhD, Academician of the Russian Academy of Sciences, Director of the Endocrinology Research Centre of the Russian Ministry of Health, Moscow; Member of the Russian Association of Endocrinologists

20. Nikankina, L.V., Cand. Sci. (Med.), Head of the Clinical Diagnostic Laboratory, Endocrinology Research Centre of the Russian Ministry of Health, Moscow; not a member of a professional association

21. Nikitinskaya, O.A., Cand. Sci. (Med.), Senior Researcher at the Laboratory of Osteoporosis, Department of Metabolic Bone and Joint Diseases, V.A. Nasonova Research Institute of Rheumatology, Moscow; Member of the Russian Association on Osteoporosis; Member of the Association of Rheumatologists of Russia

22. Petryaykin, A.V., MD, PhD, Associate Professor, Chief Researcher at the Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies of the Moscow City Health Department; Member of the Russian Society of Roentgenologists and Radiologists

23. Pigarova, E.A., MD, PhD, Director of the Institute of Higher and Additional Professional Education, Endocrinology Research Centre of the Russian Ministry of Health, Moscow; Member of the Russian Association of Endocrinologists

24. Rodionova, S.S., MD, PhD, Professor, Head of the Scientific and Clinical Center for Osteoporosis, N.N. Priorov National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health, Moscow; Presidium Member of the Russian Association on Osteoporosis

25. Rozhinskaya, L.Ya., MD, PhD, Professor, Chief Researcher at the Department of Neuroendocrinology and Osteopathies, Endocrinology Research Centre of the Russian Ministry of Health, Moscow; Presidium Member of the Russian Association on Osteoporosis, Member of the Russian Association of Endocrinologists

26. Skripnikova, I.A., MD, PhD, Head of the Department of Osteoporosis Prevention, National Medical Research Center for Preventive Medicine of the Russian Ministry of Health, Moscow; Presidium Member of the Russian Association on Osteoporosis

27. Tarbaeva, N.V., Cand. Sci. (Med.), Radiologist at the Department of Diagnostic Radiology, Endocrinology Research Centre of the Russian Ministry of Health, Moscow; not a member of a professional association

28. Tkacheva, O.N., MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Director of the Russian Gerontology Clinical Research Center (a structural subdivision of the Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation), Chief Freelance Geriatrician of the Russian Ministry of Health; President of the Russian Association of Gerontologists and Geriatricians

29. Toproptsova N.V., MD, PhD, Head of the Osteoporosis Laboratory, Department of Bone and Joint Metabolic Diseases, V.A. Nasonova Research Institute of Rheumatology, Moscow; Presidium Member of the Russian Association on Osteoporosis, Member of the Russian Association of Rheumatologists

30. Fadeev V.V., MD, PhD, Corresponding Member of the Russian Academy of Sciences, Director of the Endocrinology Clinic, I.M. Sechenov First Moscow State Medical University, Member of the Russian Association of Endocrinologists

31. Farba L.Ya., Traumatologist-Orthopedist, City Clinical Hospital No. 13 of the Moscow Healthcare Department, Moscow; Deputy Chairman and Member of the Association of Traumatologist-Orthopedists of Russia

32. Tsoriev T.T., Cand.Sc.(Med.), Endocrinologist, Consultative and Diagnostic Center, National Medical Research Center for Therapy and Preventive Medicine of the Russian Ministry of Health, Moscow; not a member of a professional association

33. Yureneva S.V., MD, PhD, Leading Researcher, Department of Gynecological Endocrinology, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Russian Ministry of Health, Moscow; Presidium Member of the Russian Association on Osteoporosis; Member of the Russian Association for Menopause

34. Yakushevskaya O.V., Cand.Sc.(Med.), Researcher, Department of Gynecological Endocrinology, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Russian Ministry of Health, Moscow; Member of the Russian Association for Menopause

Conflict of interest: the authors, experts, and reviewers declared no conflicts of interest regarding the development of these clinical guidelines.

Appendix A2. Methodology for Developing Clinical Guidelines

Clinical guidelines for the provision of medical care to patients with osteoporosis have been drawn up in accordance with the requirements for the development of clinical guidelines by medical professional non-profit organizations (Part 2 of Article 76 of Federal Law No. 323-FZ dated November 21, 2011, 'On the Fundamentals of Health Protection in the Russian Federation'), and Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, 'On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard form of clinical guidelines and requirements for their structure, composition and scientific validity of the information included in clinical guidelines.' The clinical guidelines are based on evidence-based clinical experience describing the physician's actions regarding the diagnosis, differential diagnosis, treatment, rehabilitation, and prevention of osteoporosis in postmenopausal women and men over 50 years of age.

Target audience for these clinical guidelines:

1. Endocrinologists;

2. Rheumatologists;

3. Traumatologist-orthopedists;

4. General practitioners / Internists;

5. General practitioners (family physicians);

6. Obstetrician-gynecologists;

7. Neurologists;

8. Physicians of other specialties involved in the diagnosis and management of patients with osteoporosis.

Medical professionals should follow these guidelines when making clinical decisions. At the same time, the guidelines do not replace the personal responsibility of medical professionals in making clinical decisions, taking into account the individual characteristics of patients and their preferences.

Table 1. Scale for grading levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading the grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Table 3. FRAX intervention threshold by 10-year probability (in percent) of major osteoporotic fractures equivalent to the probability of fractures in women with a history of osteoporotic fracture without other risk factors (BMI = 24 kg/m²), without BMD data [14]

Notes:

¹ Therapeutic intervention threshold – the value of the individual 10-year probability of major osteoporotic fractures at which a patient of the corresponding age, based on a combination of risk factors, is indicated to initiate osteoporosis therapy. Dual-energy X-ray absorptiometry of the lumbar spine and proximal femur may be performed solely for the dynamic assessment of treatment efficacy.

² Low fracture probability – the value of the individual 10-year probability of major osteoporotic fractures at which (and at lower values) a patient of the corresponding age, based on a combination of risk factors, is not indicated for dual-energy X-ray absorptiometry of the lumbar spine and proximal femur, and the patient does not require osteoporosis treatment.

³High fracture probability – the value of the individual 10-year probability of major osteoporotic fractures at which (and at higher values) a patient of the corresponding age, based on a combination of risk factors, is not indicated for dual-energy X-ray absorptiometry of the lumbar spine and proximal femur, and the patient unequivocally requires osteoporosis treatment.

Appendix A3.1 Characteristics of medicinal products for the treatment of postmenopausal osteoporosis

* – except for cases specified/indicated in column 1

1 – Historical background: initial registration studies used alendronic acid at a daily dose of 10 mg, ibandronic acid at 2.5 mg daily, and ibandronic acid at 20 mg intravenously every other day for 12 doses every 3 months. Treatment is currently carried out in accordance with current instructions

2 – 4.2-year study

3 – BMD adjusted for the NHANES population; the drug is included in the VJNL list (Essential Drugs List)

4 – 20-month study

# reference information (the study included various patients with high fracture risk, both with a history of fractures and with low BMD). In the presence of pathological fractures, code as Osteoporosis with pathological fracture (M80) M80.0 Postmenopausal osteoporosis with pathological fracture

Bisphosphonates (BPs)

Mechanism of action

BPs are analogues of inorganic pyrophosphates in which the oxygen atom is replaced by a carbon atom, making the molecule more stable. The P-C-P chemical bond is not enzymatically cleaved; consequently, no intermediate metabolites are formed in the human body, and the molecule is excreted unchanged by the kidneys, making glomerular filtration rate an important consideration. During bone resorption, the osteoclast engulfs BPs, most likely along with calcium and bone matrix [320]. Nitrogen-containing BPs bind to the enzyme farnesyl pyrophosphate synthase, which blocks the synthesis of farnesyl diphosphate required for the production of geranylgeranyl diphosphate. Consequently, the modification of signaling proteins essential for normal osteoclast function is halted. Thus, osteoclast function is impaired, the resorptive surface is reduced, which may subsequently lead to apoptosis [321].

Alendronic acid**

Indications for use: postmenopausal osteoporosis, osteoporosis in men, GCO.

Contraindications for use: esophageal stricture, achalasia, inability of the patient to stand or sit upright for at least 30 minutes after taking the drug, hypocalcemia, hypersensitivity to alendronic acid.

Dosing regimen: The drug is available in 70 mg tablets. Taken orally once every 7 days. Alendronic acid** should be taken in the morning on an empty stomach 30 minutes before a meal, washed down with a glass of plain water. After taking the tablet, it is important to maintain an upright body position for 30–40 minutes to prevent gastroesophageal reflux; no food or liquid other than plain water should be consumed.

Ibandronic acid

Indications for use: postmenopausal osteoporosis.

Contraindications for use. For all dosage forms: hypersensitivity to ibandronic acid or other components of the drug; hypocalcemia. For intravenous solution: pregnancy; breastfeeding period, severe renal impairment (serum creatinine >200 µmol/L (2.3 mg/dL) or creatinine clearance <30 mL/min). Use with caution (for tablets) — severe renal impairment (creatinine clearance <30 mL/min).

Dosing regimen: The drug is available in 150 mg tablets and 3 mg in 3 mL injection solutions. Tablet ibandronic acid should be taken once a month, in the morning on an empty stomach, washed down with a glass of plain water. After taking the drug, it is necessary to maintain an upright body position and refrain from eating food and taking other medications for 60 minutes. Ibandronic acid in the form of a 3 mg in 3 mL syringe is administered intravenously over 15–30 seconds once every 3 months.

Zoledronic acid**

Indications for use: postmenopausal osteoporosis, osteoporosis in men, GCO, prevention of postmenopausal osteoporosis (in patients with osteopenia), prevention of new fractures in men and women with proximal femur fractures.

Contraindications for use: hypersensitivity to zoledronic acid, other BPs, and other components of the drug, pregnancy, lactation period, childhood and adolescence under 18 years of age, severe mineral metabolism disorders including hypocalcemia; severe renal impairment (creatinine clearance <30 mL/min).

Prescription regimen: The drug is available in 5 mg/100 ml vials. It is administered intravenously via a valved infusion set ensuring a constant infusion rate over at least 15 minutes. For the treatment of osteoporosis, the administration frequency is once a year; for prevention, once every 2 years.

Safety of Bisphosphonate Treatment

Upper gastrointestinal adverse events (difficulty swallowing, esophagitis, and gastritis) occur with oral bisphosphonate (BP) preparations; intravenous BPs do not affect the gastrointestinal tract. All BPs are excreted unchanged by the kidneys and are contraindicated in patients with a GFR below 30–35 ml/min. To identify high-risk patients, blood creatinine levels must be monitored before starting treatment [322]. Intravenous BPs are characterized by an influenza-like illness (such reactions may also occur with oral tablets, but less frequently) in response to drug administration. Thus, according to clinical trial data, an influenza-like reaction (fever, arthralgia, myalgia, fatigue, etc.) was observed in 32% of cases after the first administration of zoledronic acid**, in 7% after the second infusion, and in 2% after the third administration. These symptoms typically resolve within 3 days following BP administration [322]. The use of non-steroidal anti-inflammatory and antirheumatic drugs (ibuprofen**, paracetamol**) relieves the symptoms of the influenza-like reaction.

Cases of osteonecrosis of the jaw have been reported with long-term BP use for osteoporosis. This complication is more common in the treatment of oncological diseases when high doses of BPs are administered. The risk of developing osteonecrosis of the jaw during osteoporosis treatment increases if the duration of BP therapy exceeds five years [323]. Rare complications of long-term BP treatment (exceeding five years) include atypical subtrochanteric and shaft femoral fractures. Such fractures are often preceded by thigh and groin pain, which can be bilateral. If an atypical femoral fracture is suspected, radiography of both femurs must be performed, along with MRI if necessary [225]. In some cases, surgical intervention is required for an atypical femoral fracture, but conservative management is more commonly followed. Treatment with BPs must be discontinued if such fractures occur.

Monoclonal antibody to receptor activator of nuclear factor kappa-B ligand (RANKL) (ATC M05BX Other drugs affecting bone structure and mineralization) – denosumab**.

Denosumab** is a human monoclonal antibody against RANKL [181, 182]. The drug interferes with the recruitment mechanism of active osteoclasts by acting analogously to osteoprotegerin, which under physiological conditions blocks RANKL, prevents its interaction with the receptor activator of nuclear factor kappa-B (RANK), and thus reduces the recruitment of mature osteoclasts.

Unlike BPs, denosumab** reduces the formation of osteoclasts rather than impairing the function of mature cells. Furthermore, as a biological agent, denosumab** does not accumulate in bone tissue and has no delayed effect, with a complete reversal of its effect upon discontinuation of treatment [183].

Indications for Use:

- postmenopausal osteoporosis;

- osteoporosis in men;

- GIO;

- prevention of bone mass loss and fractures in the absence of bone metastases in women receiving aromatase inhibitor therapy for breast cancer and in men with prostate cancer receiving androgen deprivation therapy [181–186].

Safety of Denosumab Use**

Based on a 3-year study involving 7,868 individuals, the drug demonstrated a favorable safety profile. Eczema (118 patients [3%] compared to 65 patients [1.7%] in the placebo group), flatulence (84 patients [2.2%] compared to 53 patients [1.4%] in the placebo group), and cellulitis (including erysipelas) in 12 patients (0.3%) compared to 1 patient (<0.1%) in the placebo group were statistically significantly more frequent in patients receiving denosumab**. Denosumab** may contribute to the development of hypocalcemia; therefore, it is important to correct vitamin D deficiency prior to initiating treatment and ensure adequate calcium intake.

Osteonecrosis of the jaw during denosumab** therapy develops extremely rarely and is observed in patients with oncological diseases involving skeletal metastases (at higher drug doses). Atypical femoral fractures are rarely associated with the use of denosumab**.

The benefits of denosumab** treatment significantly outweigh the risks of rare adverse effects.

Contraindications and Limitations of Denosumab Therapy**

Hypocalcemia, hypersensitivity to the drug. Pregnancy or breastfeeding.

Denosumab Prescription Regimen

For the treatment of osteoporosis, denosumab** is administered subcutaneously at a dose of 60 mg every 6 months. The drug is available in a pre-filled syringe.

Teriparatide**

Teriparatide** (a recombinant human parathyroid hormone fragment [1-34 PTH]) belongs to anabolic osteoporosis therapies. In this context, the anabolic effect refers to a predominant action on osteoblasts, an increase in the lifespan of bone-forming cells, a decrease in their apoptosis, an enhancement of mesenchymal stem cell differentiation toward the osteoblast lineage (via Wnt signaling), and consequently an increase in bone formation during each bone remodeling cycle, as well as the activation of modeling in specific skeletal sites, which has been proven in humans via bone biopsies [324, 325].

Prescription Regimen

Subcutaneous injections at a dose of 20 mcg once daily, every day. Teriparatide** is supplied in a glass cartridge secured in a disposable delivery device designed to deliver 28 doses. The drug must be stored in a refrigerator, but exposure to room temperature is permissible for several hours (up to 36 hours).

Indications for Use:

• postmenopausal osteoporosis in women;

• primary osteoporosis or hypogonadism-induced osteoporosis in men;

• osteoporosis with an increased risk of fractures in men and women receiving long-term systemic GCS therapy;

Adverse Events

The most frequent adverse events (in less than 10% of trial subjects) were dizziness and leg cramps [202, 326]. Moderate transient hypercalcemia (less than 2.8 mmol/l) was reported in 2% of the control group after injection and in 11% of patients receiving 20 mcg of teriparatide** [202]. The increase in calcium levels was typically observed 4–6 hours post-injection and completely normalized by 24 hours. The increase in calciuria did not differ significantly from the control group and was not associated with an increased risk of urolithiasis. Antibodies to teriparatide** were detected in 3–8% of women, but their titers decreased over time and they had no effect on BMD or calcium levels.

The use of teriparatide** in patients with moderately reduced glomerular filtration rate (30–49 ml/min) led to an increase in serum uric acid, but this was not associated with an increased risk of gout, arthralgia, or kidney stone formation [327].

Contraindications and Limitations

Hypercalcemia, primary hyperparathyroidism, Paget's disease, unexplained elevation of alkaline phosphatase, osteosarcoma, unclosed epiphyses, history of skeletal irradiation, pregnancy or breastfeeding, malignant bone tumors or skeletal metastases, allergic reaction to teriparatide** or excipients.

Strontium ranelate**

Strontium ranelate** 2 g daily in sachets demonstrated moderate anti-fracture efficacy in clinical trials (Appendix A3.1). A reduction in the risk of hip fractures was observed only in the subpopulation of patients older than 74 years with femoral neck osteoporosis. The 'dual' or mild anabolic effect of strontium ranelate** on bone tissue [318] was not confirmed in subsequent studies [328]. Tissue densification and weight gain resulting from strontium incorporation into the hydroxyapatite crystal lattice have been proposed to explain the drug's mechanism of action [328, 329].

Romosozumab

Romosozumab is a human monoclonal antibody (IgG2) produced in a mammalian cell line (Chinese hamster ovary) using recombinant DNA technology (ATC M05BX Other drugs affecting bone structure and mineralization). The approximate molecular weight of romosozumab is 149 kDa.

Mechanism of Action

Romosozumab inhibits the action of sclerostin, a factor regulating bone metabolism. It enhances bone formation and, to a lesser extent, decreases bone resorption. Animal studies have shown that romosozumab stimulates new bone formation on the trabecular and cortical bone surfaces by increasing osteoblast activity, which leads to increased trabecular and cortical bone mass and strength, as well as improved bone structure.

Indications for Use:

Treatment of osteoporosis in postmenopausal women at high risk of fractures.

Dosing regimen:

The recommended dose of romosozumab is 210 mg (administered as two subcutaneous injections of 105 mg each) once monthly for 12 months.

Adverse events:

The most frequent adverse reactions were nasopharyngitis (13.6%) and arthralgia (12.4%). Hypersensitivity reactions were observed in 6.7% of patients treated with romosozumab. Hypocalcemia was reported rarely (in 0.4% of patients treated with romosozumab). In randomized controlled trials compared to alendronate, patients treated with romosozumab experienced an increased incidence of serious cardiovascular adverse events (myocardial infarction and stroke) compared to the control group.

Contraindications and limitations:

Hypersensitivity to romosozumab and/or any of the excipients; hypocalcemia; history of myocardial infarction or stroke; age under 18 years; pregnancy and breastfeeding.

Appendix A3.2 Laboratory testing capabilities for ruling out secondary causes of osteoporosis and other metabolic skeletal diseases.

Appendix A3.3 Method for assessing vertebral body compression fractures [86, 8]

Appendix A 3.5 Additional bone densitometry technologies [136]

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

What is osteoporosis?

Osteoporosis is a disease in which bones become fragile and can break easily. Normally, bone has a porous structure; in osteoporosis, bone mass decreases and bone structure is compromised.

Who gets osteoporosis?

According to the International Osteoporosis Foundation, every third woman, and in countries with high life expectancy every second woman over the age of 50, suffers an osteoporosis-related fracture. Therefore, 80% of osteoporosis patients are postmenopausal women (after cessation of menses).

Older men (over 50) also suffer from osteoporosis, as well as patients of any age and sex with certain endocrine or rheumatic diseases, severe intestinal disorders (Crohn's disease, ulcerative colitis), post-organ transplant patients, individuals with immobility due to any cause, and patients taking certain medications long-term (antiepileptic drugs, glucocorticoids, acid-suppressive medications, etc.).

Why is osteoporosis dangerous?

In patients with osteoporosis, fractures occur with minimal trauma (a fall from standing height, sneezing, coughing, lifting heavy objects, etc.) or even without any trauma.

The most dangerous fractures associated with high mortality are hip fractures. If such a fracture occurs, surgical treatment is required.

In addition, osteoporosis causes pathological fractures of the arms (radius, humerus), lower leg bones, pelvis, clavicle, and ribs from a fall from standing height.

The most frequent pathological fractures are vertebral body fractures. A vertebral body fracture may be accompanied by back pain. The presence of a single fracture significantly increases the likelihood of subsequent vertebral fractures. Multiple vertebral body fractures lead to posture changes and a height loss of 4–5 cm or more.

How to suspect osteoporosis?

Some call osteoporosis the "silent epidemic." A patient with osteoporosis without fractures usually has no complaints. At the same time, there are fracture risk factors that help the patient and physician orient themselves. Even a patient can assess their individual 10-year probability of major fractures (FRAX).

How is osteoporosis diagnosed?

It is important for your doctor to know if you have had fractures resulting from minimal trauma after the age of 45. Sometimes the presence of such a fracture is sufficient to diagnose osteoporosis.

For early diagnosis of osteoporosis (when fractures are not yet present), the most accurate method is dual-energy X-ray absorptiometry (DXA) of the lumbar spine and proximal femur. This is a painless and safe method for assessing bone mineral density. Bone density is measured in the lumbar vertebrae, the femur, and sometimes, if necessary, the forearm. This is sufficient to assess the state of the entire skeleton. The radiation dose during this study is 10 times lower than that of a standard chest X-ray. Prior to the test, it is advisable to avoid using contrast agents. You will be asked to remove all metal objects from the areas being scanned (lower trunk, hips, forearms). Ultrasound devices (bone density measurements of the calcaneus, phalanges, etc.) are screening tools rather than diagnostic methods.

To determine the cause of osteoporosis, select the optimal drug for treatment, and for follow-up monitoring, your doctor may require blood and urine tests, as well as lateral radiography of the thoracic and lumbar spine, and occasionally spinal computed tomography or magnetic resonance imaging.

Are there treatments for osteoporosis?

Today, drug treatment for osteoporosis significantly reduces the risk of fractures and increases bone mineral density. The first treatment results can be seen after 1 year, based on the increase in bone mineral density according to X-ray densitometry. The minimum duration of continuous osteoporosis treatment in most cases is 3 years. However, in some patients, continuous treatment lasts for 5 years or more. Sometimes a physician may stop treatment and then resume therapy again. At the same time, following specialist recommendations helps prevent fractures, preserve posture, and thus significantly improve the quality of life. New drugs offer high efficacy combined with increasingly infrequent and convenient dosing. The emergence of generic drugs makes osteoporosis treatment increasingly accessible.

Warning! Drugs differ in efficacy, indications, contraindications, and their use requires medical supervision.

Can osteoporosis be prevented?

Bone health care should begin in childhood. It is especially important to maintain a healthy lifestyle during the period of peak bone mass accumulation (up to 25–30 years). The higher the "peak bone mass," the later the decline in bone mass will reach the "threshold" beyond which a fracture occurs.

For the prevention of osteoporosis, it is recommended to:

1. Consume adequate amounts of calcium and vitamin D throughout life

Dietary sources of calcium:

• 100 g of low-fat dairy products (milk, kefir, yogurt, ice cream, cottage cheese) contain 100-120 mg of calcium;

• 100 g of hard cheese can contain up to 1000 mg of calcium;

• calcium is also found in spinach, broccoli, canned fish with bones, and calcium-fortified foods (orange juice, cereals – if indicated that the product is fortified with calcium).

Vitamin D plays an important role in calcium absorption and bone and muscle health. In young people, vitamin D is synthesized in the skin under the influence of ultraviolet rays. Walking for 15–30 minutes with an exposed face and hands is sufficient to get an adequate level of vitamin D. However, in elderly people, the skin's ability to synthesize vitamin D decreases.

2. Engage in recreational sports throughout life:

Weight-bearing physical exercises (walking, running, tennis, dancing, gym workouts) are beneficial for achieving a better peak bone mass and improving bone quality in young people. These exercises are less effective in postmenopausal women for increasing bone mass. At the same time, exercises aimed at increasing muscle mass and improving balance are beneficial for preventing falls. Exhausting physical exertion, on the contrary, can lead to premature loss of bone mineral density.

3. Avoid bad habits (smoking, alcohol abuse):

Smoking negatively affects bones. Smoking women have lower estrogen levels and enter menopause earlier. Smoking leads to poorer absorption of calcium from food. People who smoke a pack of cigarettes daily usually have 5–10% less bone mass by age 50 compared to non-smokers.

Alcohol abuse (more than 2–3 established units of alcohol daily, regularly – equivalent to a standard glass of beer (285 ml), one standard serving of spirits (30 ml), a medium glass of wine (120 ml), or one serving of aperitif (60 ml)) leads to a decrease in bone density even in young men and women. Alcoholism increases the risk of fractures due to bone mass loss, nutritional deficiencies, and an increased frequency of falls.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Fracture Risk Assessment Using the FRAX Tool [3]

Name in Russian: FRAX – Fracture Risk Assessment Tool

Original name (if applicable): FRAX ®

Source (official developer website, validation publication):

https://www.sheffield.ac.uk/FRAX/tool.aspx?lang=rs

Type: rating scale

Purpose: fracture risk assessment

Contents: To calculate the 10-year probability of fracture using bone mineral density, answer the following questions.

Questionnaire:

Key (interpretation): Fracture risk assessment result in the orange zone: dual-energy X-ray absorptiometry (DXA) of the lumbar spine and proximal femur is recommended. If osteoporosis is detected (T-score ≤ -2.5), anti-osteoporosis therapy is indicated without re-evaluating fracture risk.