Fracture Nonunion (Pseudarthrosis). Delayed Fracture Healing: Clinical Guidelines

List of Abbreviations

ABT – antibacterial therapy.

AVF – external fixation device.

AO – Association of the Osteosynthesis.

ATOR – All-Russian Public Organization "Association of Traumatologists and Orthopedists of Russia".

BBK – tibia (tibular bone).

VTEO – venous thromboembolic complications.

DMBS – distal tibiofibular syndesmosis.

DOKG – distal leg bones.

RTA – road traffic accident.

PJI – periprosthetic joint infection.

knee – knee joint.

SCT – spiral computed tomography.

medications – medications.

HDL – high-density lipoproteins.

LDL – low-density lipoproteins.

PT – physical therapy.

Russian Ministry of Health – Ministry of Health of the Russian Federation.

MDT – multidisciplinary rehabilitation team.

ICD-10 – International Statistical Classification of Diseases and Related Health Problems, 10th Revision.

MRI – magnetic resonance imaging.

LMWH – low-molecular-weight heparin from group B01AB Heparin group.

NSAIDs – nonsteroidal anti-inflammatory drugs from group M01A Nonsteroidal anti-inflammatory and antirheumatic products.

BV – blood volume.

DLF fractures – distal leg fracture.

ATS – antitetanus serum.

TIG – tetanus human immunoglobulin.

INITIAL surgical debridement – primary surgical wound debridement.

SCT – spiral computed tomography.

TIA – transient ischemic attack.

RF – risk factors.

PRM – physical and rehabilitation medicine.

PT – physical therapist.

FS – functional status.

TENS – transcutaneous electrical nerve stimulation.

SAP – surgical antibiotic prophylaxis.

LCP – Locking Compression Plate – locking compression plate.

MIPO – Minimally Invasive Plate Osteosynthesis – minimally invasive plate osteosynthesis.

ORIF – Open Reduction Internal Fixation – open reduction internal fixation.

Terms and Definitions

Allograft – bone tissue fragment from another human (donor), typically cadaveric, that has undergone preservation.

Autograft – a fragment of the patient's own bone harvested from a donor site for transplantation to fill a bone tissue deficit (bone defect).

Bilocal compression-distraction osteosynthesis – fragment osteotomy and bone transport (controlled, dosed movement of the created fragment).

Defect-diastasis – persistent widened interfragmentary gap with no tendency to be filled with callus.

Delayed fracture union – consolidation period exceeding up to twice the accepted norm, or absence of dynamics in closing the interfragmentary gap with callus without the formation of terminal plates.

Fracture union – mutual connection of fragments by living bone tissue as a result of the successful completion of reparative regeneration.

Bone fragment – a part of the bone separated as a result of damage from trauma, surgery, or a destructive process.

Modelling resection – excision of a part of the bone to ensure maximum fragment contact in the fracture (non-union) zone or to eliminate joint impingement.

Percutaneous osteosynthesis – a method of surgical reduction and fixation of bone fragments using compression-distraction external fixation devices.

Monolocal compression osteosynthesis – creation of controlled compression or distraction in the problem area (zone of interest) using an external fixation device.

Load – mechanical force applied to the limb, bone, and fixator-bone system during treatment, typically recurring at a constant periodicity (cyclically).

Impaired fracture union – changes in bone tissue reparative regeneration leading to a decrease in its rate, cessation, or formation of callus insufficient to perform the mechanical function.

Non-union (pseudoarthrosis) – cessation of consolidation manifested radiologically by the formation of terminal plates closing the fracture surfaces.

Orthopedic implant – a device implanted into the human body to connect fragments and temporarily compensate for lost bone strength (fixator, graft, their components and combinations, and in some cases an endoprosthesis).

Structural strength – the ultimate load at which the fixation properties of the structure begin to fail or it breaks.

Revision surgery – a repeat operation at the same site as the primary operation, aimed at achieving the goal of the primary surgery with the maximum possible restoration of limb function.

Re-osteosynthesis – revision osteosynthesis – repeat osteosynthesis at the same location.

Fixation stability – the resistance of the fixator-bone system to external loads, allowing it to maintain the constancy of the mutual orientation of fragments and the optimal distance between them under physiological loading of the damaged segment.

External fixator – an orthopedic device containing an implant (a transosseous or extracortical element protruding through the skin, reaching the bone or embedded into it) and an external (non-implantable) support connecting bone fragments through transosseous elements in the treatment of fractures, pseudoarthrosis, or gradual lengthening (deformity correction) of a segment.

Internal fixator – an orthopedic implant implanted under the patient's skin and connecting bone fragments in the treatment of fractures, deformities, or pseudoarthrosis.

Fixation – a state in which complete immobilization of fragments is achieved or micro-mobility is preserved that does not prevent fracture healing under conditions of relative stability.

See also section 1.1 for the definition of delayed fracture union and fracture non-union [pseudoarthrosis]; section 1.5 for definitions of various types of fracture non-union [pseudoarthrosis]; section 1.4 for specific coding of delayed fracture union and fracture non-union [pseudoarthrosis] according to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10); and the List of Abbreviations section for abbreviations used.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Normal bone tissue function requires a balance of osteoconduction, osteoinduction, and osteogenesis. In the case of a fracture, adequate stabilization of bone fragments and their adequate vascularization are also required. However, the conditions described above are not always fully met, leading to various types of bone fragment non-union [65].

Delayed consolidation is a condition where the average time required for the healing of a fracture at a given location has passed, but clinical and radiological signs of healing are not determined. In delayed consolidation, callus formation more commonly occurs via "secondary healing" and over a longer period.

Fracture non-union or bone pseudoarthrosis – a pathological condition characterized by impaired consolidation of bone fragments after a fracture within the expected timeframe, leading to the formation of a mobile joint between them. The degree of pathological mobility is determined by the form of non-union (pseudoarthrosis).

These clinical guidelines cover only post-traumatic isolated variants of delayed fracture union or fracture non-union (pseudoarthrosis) of long bones of the limbs at the diaphyseal or metaphyseal level in adults and children, excluding birth trauma.

Issues of bone defect replacement and correction of post-traumatic deformities are also not covered by these clinical guidelines.

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

The etiology and pathogenesis of delayed fracture union and non-union (pseudoarthrosis) of long bones of the limbs can be considered together, as they are essentially successive stages of compromised bone injury healing.

Pseudoarthrosis (post-traumatic) is a form (or stage) of imperfect osteoregeneration. While delayed consolidation can be thought of as a condition where the average healing time after a fracture has passed, pseudoarthrosis is a condition where twice the average healing time has passed since the fracture with no signs of consolidation. This division, despite being somewhat arbitrary, is of great clinical importance. Delayed consolidation allows for hope of healing. A diagnosis of pseudoarthrosis rules out healing without additional stimulation and is effectively an indication for surgery [1, 2].

Systemic factors delaying fracture healing include endocrine diseases and metabolic disorders, especially electrolyte disorders, age-related changes, chronic vascular diseases of the limbs, and regular use of glucocorticoids and cytostatics.

Local factors affecting consolidation processes include unsatisfactory bone fragment position after osteosynthesis, soft tissue interposition, poor blood supply in the fracture zone, lack of functional loading, infection, osteoporosis, excessively traumatic surgery violating periosteal integrity, reaction to implants, and removal of the blood clot between fragments resulting from direct open fragment reduction. Specific causes of delayed union and pseudoarthrosis formation include errors and complications during fracture treatment:

• errors in conservative treatment – inadequate duration and quality of limb segment immobilization, fragment overdistraction on skeletal traction;

• surgical errors – unstable fixation and fracture reduction, devitalization and/or resection of fragments during surgical debridement, infectious complications;

• errors of postoperative rehabilitation – inadequate periods of limb immobilization after unstable internal fixation, early removal of the bone fixator, untimely load on the limb [3-5].

Thus, a number of systemic and local factors influence fracture healing. The presence of systemic factors must be taken into account when choosing a fracture treatment method. When planning primary osteosynthesis, taking into account the severity of the injury and the patient's systemic factors, it is necessary to ensure a sufficient level of fixation stability while maintaining adequate tissue vascularization in the fracture zone.

Considering all of the above, it can be concluded that the main significance in the pathogenesis of delayed fracture healing and the formation of a bone pseudoarthrosis is held by circulatory disorders and the presence of mobility in the fracture zone. The overall intensity of blood supply depends on the patient's age; in this regard, the age factor plays a major role: for example, a femur fracture in early childhood heals in 3-4 weeks, while in adults it takes 3-4 months. The severity of the sustained injury is also of great importance.

In general, a fracture damages the blood vessels supplying the bone, and a spasm of the main arteries and their branches (up to arterioles) occurs. Subsequent surgical intervention can lead to impaired blood supply due to the detachment of soft tissues from the bone. With the mobility of fragments, constant traumatization of the structures of the developing callus occurs, including newly formed vessels. This inevitably leads to a slowdown in osteogenesis and a decrease in the strength of the union of fragments, up to their repeated separation. Prolonged persistence of fragment mobility in the fracture zone can lead to the replacement of bone tissue with fibrous tissue, and then cartilage tissue.

Mobility and axial loading during the contact of bone fragments and their preserved reparative capacity lead to bone formation along the lateral surfaces of the fragments with their significant thickening, but without bone fusion between them. Thus, hypertrophic or hypervascular pseudoarthrosis is formed. Common to them is the predominance of bone formation and remodeling processes over osteolysis processes.

Exposure of fragments over a significant length, their divergence excluding contact and loading from the very beginning, and massive destruction of the surrounding soft tissues lead to insufficient blood supply to the fracture zone. The intensity of the reparative reaction under these conditions decreases and gradually fades, and resorption processes begin to prevail. The ends of the fragments become thinned and pointed. This is how hypotrophic or hypovascular pseudoarthroses are formed, in which bone resorption prevails over neoosteogenesis [1, 3-7].

1.3 Epidemiology of the Disease or Condition

Delayed union of bone fragments in fractures of the long bones of the limbs accounts for 15 to 50%, and the frequency of pseudoarthrosis formation varies from 4 to 33%. In the structure of long bone injury consequences, femoral pseudoarthroses account for 10-30%, leg bones – 15-50%, humeral bone – 1-10%, ulnar bone 5-12%, radial 1-3%. According to various authors, revision surgical procedures associated with delayed fracture healing and pseudoarthrosis formation occur in 3-17% of cases of the total number of trauma and orthopedic operations accompanied by the implantation of devices into the bones of the limbs [1, 8, 9].

Delayed fracture consolidation in children is a rare complication, but its risk increases with age, especially in adolescent boys and with certain types of fractures (femoral neck fracture, scaphoid fracture, lower leg bone fractures). The overall risk of fracture nonunion in children under 15 years of age is about 0.2% (1 case per 500 fractures), and in adolescents aged 15–19 years, it is 0.35%. In boys aged 15–19 years, the risk reaches 0.45% (1 in 222 fractures) [84].

1.4 Features of Coding the Disease or Condition

This clinical guideline provides information on bone integrity disorders (general group M84) considered in these guidelines:

• M84.0 Malunion of fracture

• M84.1 Nonunion of fracture (pseudoarthrosis)

• M84.2 Delayed union of fracture

Pseudoarthrosis after fusion or arthrodesis (M96.0) and congenital pseudoarthroses (Q74.8) are not coded with the above codes and are not considered in this clinical guideline.

1.5 Classification of the disease or condition

Below are some classifications of delayed fracture healing with pseudoarthrosis formation used in our country [1-3]. In clinical practice, for choosing treatment tactics, the classification taking into account the clinical and radiological picture and the presence of purulent complications is of the greatest importance.

1. By etiology:

• Congenital

• Pathological

• Traumatic

2. By the nature of the injury:

• Non-gunshot origin

• Gunshot origin

3. By clinical and radiological picture:

• Delayed fracture healing or developing pseudoarthrosis. It occurs after the period required for fracture healing has elapsed. It is characterized by the onset of pain at the fracture site, tenderness on palpation and movements in the joint; radiographs clearly show a fracture "gap" in the presence of periosteal callus.

• "Tight" (slit-like, fibrous). It is characterized by the formation of coarse fibrous tissue between the fragments, mild pathological mobility (in the absence of diastasis), and a narrow gap is visible on radiographs.

• Necrotic. It occurs in gunshot fractures when the blood supply to the bone is disrupted, and in fractures prone to bone necrosis (femoral head after femoral neck fracture, body of the talus after transverse fracture of the talar neck, medial part of the carpal scaphoid after transverse fracture):

  • with aseptic necrosis of the ends of the fragments,

  • with necrosis of fragments and the presence between them of a freely lying or fragment-attached necrost (bone sequestrum).

• Pseudoarthrosis of the bone regenerate. Observed after tibial osteotomy as a result of excessive distraction and unstable fixation with apparatuses during segment lengthening.

• True (neoarthrosis). It develops more often in single-bone segments where pathological mobility is present. The fragments are smoothed out and covered with fibrocartilage with areas of hyaline cartilage. A space filled with fluid forms between the fragments, and a capsule similar to a joint capsule forms around the ends of the fragments.

• With a bone substance defect, i.e., neoarthrosis in the form of a defect.

4. By the degree of osteogenic activity:

• Hypertrophic. Pseudoarthroses with bone tissue proliferation at the ends of fragments. They develop in patients with insufficient fixation stability of bone fragments and a preserved vascular network of surrounding tissues.

• Normotrophic.

• Hypotrophic (avascular). Pseudoarthroses with impaired blood supply and poor bone formation. The development of hypotrophic nonunion is caused either solely by the biological component (circulatory deficit in the fracture zone) or by a combination of biological factors with mechanical ones (poor-quality fragment fixation) [65].

This classification is of great clinical importance, since in hypertrophic nonunions there is only excessive mobility between the fragments, and for fusion it is sufficient only to adequately stabilize the fracture, which can be done without opening the nonunion zone. Normotrophic and, to a greater extent, hypotrophic nonunions require stimulation of osteogenesis by performing bone autoplasty or using modern products with osteoconductive and osteoinductive activity [65].

5. By the presence of purulent complications:

• uncomplicated;

• infected.

1.6 Clinical presentation of the disease or condition

Main clinical signs: pain in the fracture area, pathological mobility, impaired limb function, limb deformation and shortening, restriction of mobility of adjacent joints, decreased muscle strength and atrophy, impaired limb blood supply. The degree of manifestation of these signs depends on the stage of the pathological process.

Post-traumatic (acquired) false joint occurs at the site of a fracture, accompanied by more or less pronounced bone mobility in an unusual location. Passive pathological mobility of the limb segment is observed, ranging from rocking (in fibrous false joints) to full mobility in all planes (in extensive defects). When the limb is unloaded, there is no pain in the area of the false joint or it is insignificant. This distinguishes a false joint from ununited fractures, where mobility is insignificant and pain always occurs. If a false joint forms on one of the two bones of a limb segment (e.g., the radius while preserving the integrity of the ulna), symptoms may be absent or mild. The formation of false joint signs usually occurs by twice the average bone healing time; prior to this, the pathology should be regarded as an ununited fracture, which is a potential precursor to a false joint. By this time, limb deformation and shortening begin to occur and progressively increase. Deformations in acquired false joints can be quite varied, but they are typical for certain locations. Thus, for a false joint of the bones of the lower leg, recurvation combined with varus or valgus curvature is characteristic; for the femur — antecurvation and varus deformity ("riding breeches"); for the forearm with radius defects — traumatic clubhand with valgus deviation of the hand and dislocation of the ulnar head. In a false joint following a Montezzi fracture, elbow joint deformation develops due to dislocation of the radial head and angular deformation of the ulna open posteriorly. Limb segment shortening in a false joint can vary. In childhood, shortening is always greater. Pathological mobility, deformation, and shortening also determine the main functional impairments: for the lower extremities, this is impaired weight-bearing capacity, forcing the patient to use additional support devices (crutches, a cane, orthopedic braces); for the upper extremities, it is a decrease in muscle strength due to the approximation of muscle origin and insertion points, their scar degeneration, and the development of secondary contractures. As a result of the trauma itself, surgical interventions for the fracture and false joint, purulent complications, and static changes due to deformation and shortening, physiological and morphological changes occur in all tissues of the injured limb, constituting a pathological symptom complex (scar changes in the skin, dystrophic changes in muscles and nerves, circulatory disorders including persistent edema, spasm of major and small vessels, autonomic-trophic changes, disuse bone atrophy, contractures, and joint ankylosis).

A special place is occupied by pseudoarthroses complicated by osteomyelitis. Most often, terminal osteomyelitis of fragments occurs with the formation of sequestra of various sizes. In the presence of sequestra, in most cases there are fistulas in the pseudoarthrosis area. Small sequestra can be located between the fragments, while large sequestra occupy a significant part of one or both fragments and maintain suppuration for a long time.

X-ray examination makes it possible to perform differential diagnosis between a nonunion and delayed fracture union. The main X-ray signs of a nonunion include: absence of a bone callus connecting the ends of both fragments; rounding and smoothing of the fragment ends, sometimes their conical shape developing as a result of bone resorption and the absence of bone substance formation processes (atrophic nonunion); expansion of the ends of bone fragments due to newly formed bone tissue while maintaining a gap between the fragments (hypertrophic nonunion); obliteration of the medullary cavity at the ends of the fragments (development of a closing plate), indicating the cessation of regenerative processes on the part of the bone marrow and endosteum. Obliteration of the medullary cavity occurs as a result of the formation of a dense bone substance similar to the compact bone substance, the thickness and density of which depend on the duration of the nonunion and its functional load. Thus, a nonunion in an X-ray image acquires a characteristic picture: the "articular" ends of the fragments are somewhat expanded, their structure is sclerotically altered. Often, the end of one fragment has a hemispherical shape and resembles an articular head, while the end of another is concave like an articular socket. At the same time, the "joint space" is clearly visible on radiographs in both projections. Thickening of the bone fragments in the area of the nonunion gap, uneven contours of the gap itself, and its small width are characteristic of the hypertrophic type. The nonunion gap of this type often has a complex surface shape, and not all areas of the gap are parallel to the path of the X-rays. On the radiograph in such cases, the gap is far from entirely visible, creating an illusion of fracture union; in such cases, computed tomography helps with diagnosis, as it allows assessing the presence or absence of bone union in various areas of the fracture and determining resorption zones in the area of implants [1-3, 10, 11].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis of delayed fracture union and nonunion of long bones of the extremities: the diagnosis is made based on anamnestic data and clinical manifestations (pathological mobility, curvature of the limb axis, its shortening, pain upon load). However, all these symptoms are optional and may be absent in a number of patients. This is more common in fibrous hypertrophic "tight" nonunions with low fragment mobility, for example, a nonunion of the tibia with a healed fibula. The most informative diagnostic method is X-ray examination, in the absence of conditions requiring coding by other ICD-10 codes (see section 1.4). If there are doubts about the presence of union according to radiography data, computed tomography of the injury zone must be performed [1-3]. To assess the disease status, the questionnaires specified in Appendices G1 and G2 can be used.

2.1 Complaints and Anamnesis

2.2 Physical Examination

2.3 Laboratory Diagnostics

Comments: the detection rate of infection in patients with long bone nonunions exceeds 50% [102]. According to the majority of specialists, CRP is the most sensitive serum marker for detecting an infectious process in the area of delayed fracture union or long bone nonunion. However, its diagnostic significance is limited, and the obtained results must be interpreted prudently, since a CRP level within reference ranges is not a criterion that excludes infection [103].

Comments: currently, isolating the same microorganisms twice from the fracture or osteosynthesis area is generally considered one of the absolute signs of fracture-related infection (FRI) [108, 109]. The detection rate of latent FRI in patients with, for example, atrophic nonunions is 57% [110].

• If an infectious process is suspected in patients of all groups with delayed fracture union or nonunion of long bones of the extremities, it is recommended, provided technical feasibility, to perform an urgent intraoperative pathological and anatomical examination of the surgical material (perimplant tissues) (pathological and anatomical examination of bone biopsy (surgical) material and/or pathological and anatomical examination of synovial membrane biopsy (surgical) material and/or pathological and anatomical examination of joint bursa or joint capsule biopsy (surgical) material) to confirm or rule out an infectious process and potentially modify surgical treatment tactics [111, 112].

GSI CLEL 4Grade of Recommendations C (Level of Evidence – 4).

Comments. The presence of acute inflammation on urgent pathological examination of frozen periprosthetic tissue samples, described by the pathologist, highly indicates the presence of infection. Currently, histological criteria have been developed to confirm the infectious process in pre-implant tissues. Thus, according to Feldman's criterion, the detection of more than 5 neutrophils in at least 5 high-power fields ($\times 400$ magnification) indicates periprosthetic joint infection (PJI) [112].

2.4 Instrumental Diagnostics

Comments: the purpose of computed tomography is to: determine the shape, size, and location of the callus, osteophytes, ossifications, and bone defects; determine the exact dimensions of the bone (diameter of the medullary cavity, cortical thickness, transverse and longitudinal dimensions in millimeters) for the correct selection of the proper type and size of the implant; determine the degree of callus development and the volume of bone defects requiring bone grafting. Furthermore, computed tomography data make it possible to estimate the volume of required resections and bone graft material, and to determine the projection lines for the location of implant fixation elements (if present) for proper surgical planning of implant removal, installation of a new one, and performance of the reconstructive-plastic component of the intervention. In addition, computed tomography makes it possible to assess the density of compact and cancellous bone tissue in the fracture fragment contact zone and the placement sites of the locking elements of the new implant, including the severity of osteoporosis in terms of the reliability of available fixation means.

For an unambiguous detailed interpretation of the injury pattern, three-dimensional reconstruction based on spiral CT is performed, including the use of computer-graphic removal of overlapping structures and graphical axis construction to accurately measure deformation angles in all planes, including torsion [14, 15].

2.5 Other Procedures

2.5.1 Invasive diagnostic procedures

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

3.1 Treatment of delayed and ununited fractures (pseudarthrosis)

Comments: in the presence of contraindications for surgical intervention, immobilization is recommended (application of an immobilization bandage for bone fractures) of the injured segment until fracture healing or resolution of relative contraindications. In the presence of absolute contraindications to surgical intervention, immobilization of the segment (application of a plaster cast for bone fractures) is recommended until full or satisfactory limb function is restored using non-invasive methods of osteogenesis stimulation [4, 17, 18].

Comments: the main tasks that must be accomplished during the surgical treatment of patients with delayed union and nonunion of fractures (pseudarthrosis) of long bones of the extremities are the restoration of conditions for callus formation and the provision of early functional rehabilitation of the injured limb [20-24]. All applied and described below methods of surgical treatment must, taking into account local and systemic factors affecting fracture consolidation processes, ensure the maximum balance of the biological and mechanical components of osteosynthesis [65].

Comments: since in hypertrophic nonunion biological processes in the fracture zone proceed normally with adequate blood supply, as evidenced by a pronounced periosteal reaction, it is necessary to target the mechanical component, i.e., perform better internal fixation. The fixation technique can vary. Plate osteosynthesis involves bridging the fracture zone with long plates installed using the bridging fixation technique (the following implants are used when performing plate osteosynthesis: non-absorbable, sterile bone fixation plate with screws***, non-absorbable, non-sterile bone fixation plate with screws***, non-absorbable, sterile orthopedic bone screw***, non-absorbable, non-sterile orthopedic bone screw***). Intramedullary osteosynthesis is performed using the medullary canal reaming technique (the following implants are used when performing intramedullary osteosynthesis: non-absorbable orthopedic bone rod***, absorbable orthopedic bone rod***, non-sterile femoral intramedullary nail***, sterile femoral intramedullary nail***, non-sterile humeral intramedullary nail***, sterile humeral intramedullary nail***, sterile tibial intramedullary nail***, non-sterile tibial intramedullary nail***, non-absorbable, sterile orthopedic bone screw***, non-absorbable, non-sterile orthopedic bone screw***). Reaming helps increase the diameter of the medullary canal, which allows the use of a larger-diameter fixator and increases the contact area between the nail and the bone. In addition, reaming is one of the bone grafting options and has a stimulating effect on osteorepair processes [24].

In the treatment of delayed diaphyseal union of long limb bones (taking into account the patient's general condition and soft tissue compromise), compression-distraction osteosynthesis is recommended to reduce surgical risks. In this approach, an external fixation device is used to immobilize the fragments, and closed reduction is performed intraoperatively. To stimulate callus formation, adjustable compression and distraction are applied during the fixation period in the apparatus; if necessary, percutaneous revascularizing osteoperforation or longitudinal osteotomy (bone reconstruction, bone osteotomy using internal fixators and external fixation devices, and/or bone reconstruction, bone osteotomy) of the fragment ends is also performed [29, 30].

The Ilizarov method is one of the modern techniques used to restore bone integrity. Its main advantages include the formation of new viable bone through distraction osteogenesis, a high fusion rate, and functional use of the limb throughout the treatment period. The rigidity of fixation in the "apparatus-bone" module—and consequently the ability to control fragment position during bone defect replacement—depends on the ring diameter of the apparatus, the distance from the bone to the ring, the tension degree, the diameter of the wires, their number, and their relative arrangement. Therefore, when selecting the apparatus, special attention should be paid to the diameter of the rings and arcs. The optimal ring diameter is considered to be when the distance from the skin surface to the inner circumference of the support ranges from 2 to 2.5 cm. In this case, the corrugation of soft tissues during the compression of fragments at their contact site must be taken into account.

In children with hypertrophic pseudarthrosis, techniques involving compression-distraction devices aimed at correcting all types of segment deformations and stimulating osteogenesis can also be used [85].

When using internal implants for fractures and non-unions at the bone diaphysis level, intramedullary devices are one of the methods of choice. In children with active growth plates, preference is given to elastic intramedullary nails with insertion points that avoid affecting the physis. The presence of an intramedullary implant provides fragment stability, and irritation of the endosteum stimulates osteogenesis. In older children, locked osteosynthesis with medullary canal reaming is recommended, but without open exposure of the pseudarthrosis site [86, 87, 88].

Comments: such interventions are frequently revision procedures; therefore, the first step is to remove the previously installed failed implant (removal of a foreign body from the bone, intramedullary metal implants and/or removal of a foreign body from the bone, extramedullary metal implants), followed by reconstructive-plastic restoration of the articulating bone structures and fracture osteosynthesis [11, 21, 31, 32].

Removal of a failed implant is in most cases not technically difficult. For error-free removal, the same instruments used during implant insertion, or fully compatible ones, should be used. In some cases, the removal of the failed fixator may turn out to be the most laborious part of the operation. This is facilitated by improper implantation technique, damage due to misuse, and the development of ossification over the implant, which create a number of difficulties (damage to the screw recess in the plate, deformed locking screw in the intramedullary nail, deformation and jamming of the intramedullary nail) requiring special techniques and instruments.

In any case, when planning a revision surgery, preparation for fixator removal must be carried out with the utmost care and selection of the full range of additional instruments and power equipment available in the clinic. This should make it possible to destroy the screw (carbide drills), remove it in parts (screw extraction forceps and bone nibblers), perform a longitudinal osteotomy (oscillating saw and osteotome), apply retrograde force to the nail fragment (rigid and flexible impactors), and break the body of the intramedullary nail using a carbide drill to weaken the nail so it breaks at the stress riser, along with hollow reamers of various diameters to destroy bone cement and pass around ingrown elements. The operating room must be equipped with adequate X-ray control, and when working with intramedullary nails, an image intensifier (C-arm) with an operating radiologic technologist is mandatory [16, 25, 33].

After removing failed metal implants in normo- and hypotrophic non-unions, it is necessary not only to perform osteosynthesis but also to ensure the stimulation of osteogenesis. In the presence of limited bone defects, their replacement with synthetic, biological materials, or autologous bone is indicated.

An osteoconductive effect can be achieved through the use of various scaffolds (hydroxyacetate, calcium phosphate, tricalcium phosphate, calcium carbonate, etc.) (bone matrix implant, synthetic***, bone matrix implant, animal-derived, resorbable***, bone matrix implant, synthetic, antibacterial***, bone matrix implant, animal-derived, non-resorbable***, bone matrix implant, composite***, bone matrix implant of human origin***). Stimulation of osteogenesis can be achieved through the implantation of substances containing living stimulating proteins (bone morphogenetic proteins, platelet-derived growth factor, vascular endothelial growth factor, basic fibroblast growth factor, demineralized bone matrix, and others). To obtain an osteogenic effect, the presence of living progenitor cells or mature bone cells contained in the autograft is required. When using composite materials, their properties are determined by the properties of their constituent components.

Autologous bone is the "gold standard" of bone grafting as it possesses osteoconductive, osteoinductive, and osteogenic properties, making it the preferred method in the surgical treatment of normo- and hypotrophic non-unions [28, 35, 37, 65].

Reconstruction of articular surfaces in the treatment of ununited fractures (pseudarthroses) of long tubular bones involves restoring the blood supply to the fragments and creating a contact area between the fragments sufficient for callus formation. To achieve the above, it is recommended to perform modeling resection of the fragment ends down to bleeding bone, restore the patency and diameter of the medullary canal, remove pathologically altered sclerosed bone tissues, followed by replacement of the bone mass deficit with bone grafting [1, 11, 16, 21, 25, 33].

Bone grafting in the treatment of ununited fractures (pseudarthrosis) of long tubular bones is performed to increase the contact surface between fragments, increase bone mass in the pathology zone, or replace the missing part of the bone, including to increase fixation stability. In the treatment of sequelae of peri- and intra-articular fractures, bone graft material is used in the form of massive load-bearing grafts.

Bone autografting is the most effective method—transplantation of the patient's own bone tissue harvested from a donor site and transplanted into the recipient bed, which is the prepared bone defect area. The optimal donor site is the iliac crest, which allows harvesting an autograft up to 10 cm in size containing both compact and cancellous bone tissue. The advantages of autologous bone from the iliac crest are its high osteogenic potential, large possible graft size, absence of fracture risk at the donor site, and relatively superficial location of the iliac bone. The massive graft is fixed to the donor bed with a compression screw or an installed device. For small bone defects, methods of harvesting donor bone from the epiphyses of long bones adjacent to the surgical area are effectively used [16, 21, 28, 35-37].

The diaphyseal part of the fibula can also be used as a free or vascularized autograft [38, 39].

The use of allografts is less effective because a significant portion of the transplanted material is resorbed during callus formation, especially when used as an onlay graft. Therefore, it is recommended to seal the area of the replaced defect by plugging the medullary canals on one side and placing a hemostatic sponge over the bone-plastic material. The incorporation of cancellous allograft bone, particularly when replacing intraosseous defects, proceeds more fully and with lesser bone mass loss: the graft gradually remodels and is replaced by the patient's newly formed bone tissue. The advantage of allogenic material is the absence of physical limitations regarding the volume of material. Therefore, when large volumes of bone grafting are required, it is advisable to use it independently (into the cavity) or as an adjunct to autografts, the amount of which proves insufficient. Disadvantages include the cost (which is higher than harvesting an autograft) and relatively lower osteoinductive properties [16, 28, 37, 40-42].

To additionally stimulate fracture healing processes, revascularizing osteoperforation can be used, which is performed by drilling several channels through both fragments using a thin drill or K-wire. Proponents of this method believe that these channels allow vessels to grow into the nonunion zone. Opponents note that any bone drilling is accompanied by thermal injury to the canal walls, which, when performed in large numbers, leads to an excessive volume of necrotic bone tissue in the focus that does not participate in reparative osteogenesis. Longitudinal osteotomy of the fragment ends can serve as an alternative method for local stimulation of osteogenesis. Prior to longitudinal osteotomy, the periosteum is detached above and below the nonunion zone for a length of no more than 3 cm; then, a longitudinal split of the fragment ends is performed through the pathological zone in two mutually perpendicular planes, thereby creating an additional focus of osteogenesis [1, 11, 16, 28].

Osteosynthesis in the treatment of ununited fractures (pseudoarthrosis) of the long bones of the extremities implies the elimination of all types of displacements and deformities with the restoration of conditions for bone tissue consolidation: sufficient contact surface and bone mass while maintaining the viability of the mating fragments, and ensuring stable and reliable fragment fixation. Osteosynthesis is almost always performed via an open approach to the bone tissue of the problematic focus. In this case, after removing the previously installed implant (if present), the condition of the bone tissue is assessed, the problem zone is debrided, and a new implant is installed. Preference is given to robust and reliable constructs with the fixation elements located outside the areas of bone tissue damage [1, 16, 21, 28].

When an ununited fracture (pseudoarthrosis) is localized in the metaphyseal zone (periarticular and intraarticular lesions), it is recommended to use periarticular locking plates of sufficient length with angular stability of the fixing screws (plate, bone, fracture fixation, with screws, non-absorbable, sterile***, plate, bone, fracture fixation, with screws, non-absorbable, non-sterile***, screw, bone, orthopedic, non-absorbable, sterile***, screw, bone, orthopedic, non-absorbable, non-sterile***) for fragment fixation [22, 25, 31, 34].

When an ununited fracture (pseudoarthrosis) is localized in the diaphyseal zone, it is recommended to use intramedullary devices with interlocking for fragment fixation (rod, bone, orthopedic, non-absorbable***, rod, bone, orthopedic, absorbable***, nail, intramedullary, femoral, non-sterile***, nail, intramedullary, femoral, sterile***, nail, intramedullary, humeral, non-sterile***, nail, intramedullary, humeral, sterile***, nail, intramedullary, tibial, sterile***, nail, intramedullary, tibial, non-sterile***, screw, bone, orthopedic, non-absorbable, sterile***, screw, bone, orthopedic, non-absorbable, non-sterile***). To create conditions for tibial fracture compression, it is recommended to perform a fibular resection over a length of 1.5–2 cm at the level of the tibial injury. During osteosynthesis of long tubular bones of the upper extremities, intramedullary osteosynthesis is performed with primary fracture compression and static interlocking (rod, bone, orthopedic, non-absorbable***, rod, bone, orthopedic, absorbable***, nail, intramedullary, femoral, non-sterile***, nail, intramedullary, femoral, sterile***, nail, intramedullary, humeral, non-sterile***, nail, intramedullary, humeral, sterile***, nail, intramedullary, tibial, sterile***, nail, intramedullary, tibial, non-sterile***, screw, bone, orthopedic, non-absorbable, sterile***, screw, bone, orthopedic, non-absorbable, non-sterile***) [1, 25, 26, 28, 31, 34, 43-46].

In younger children, the use of elastic intramedullary nails of the required diameter is indicated in the treatment of hypotrophic pseudoarthrosis with preliminary resection of non-viable bone tissue and autologous bone grafting from the iliac crest.

In the treatment of severe defects of the diaphysis of long tubular bones or the formation of hypotrophic pseudoarthrosis, the Ilizarov bone transport technique can be used, either independently or in combination with the Masquelet technique [89, 90, 91, 92].

To reduce the surgical risks of patient deterioration, the treatment of ununited fractures (pseudoarthrosis) of the long bones of extremities under conditions of chronic bone tissue inflammation (post-traumatic osteomyelitis), including prolonged remission and infectious complications of prior surgical interventions, is recommended to be carried out via monolocal compression-distraction osteosynthesis using an external fixation device for fragment stabilization. The surgical procedure may also be performed in a closed reduction mode [1, 26, 29, 30].

• All patients with infected fracture nonunion are recommended to undergo radical surgical debridement of the infection focus with biological material sampling for bacteriological identification of the pathogen and determination of antibiotic susceptibility in order to subsequently prescribe targeted therapy and eradicate the infection [67, 68, 69].

GCR BLEL 3Grade of Recommendations B (Level of Evidence Evidence – 3).

• All patients with infected fracture nonunion are recommended to undergo external fracture fixation during radical surgical debridement of the infection focus to stabilize bone fragments for fracture healing and create favorable conditions for infection eradication [67, 68, 69].

GCR BLEL 3Grade of Recommendations B (Level of Evidence Evidence – 3).

• Patients with pseudoarthrosis of the proximal humeral metaphysis with a bone tissue defect are recommended surgical treatment—total shoulder arthroplasty to improve upper extremity function and eliminate pain syndrome [2, 6, 47].

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

Comments: there are several options for shoulder arthroplasty: hemiarthroplasty, total anatomic shoulder arthroplasty, and reverse shoulder arthroplasty (the following implants are used in shoulder arthroplasty: uncapped proximal humeral endoprosthesis stem***, press-fit proximal humeral endoprosthesis stem***, humeral head endoprosthesis fixed with a stem***, partial shoulder joint endoprosthesis***, total shoulder joint endoprosthesis***, bipolar partial shoulder joint endoprosthesis***, glenoid shoulder joint endoprosthesis component***, anchor-type shoulder joint endoprosthesis head***, humeral endoprosthesis centering device***, total reverse shoulder joint endoprosthesis***, polyethylene reverse shoulder joint endoprosthesis cup***, reverse shoulder joint endoprosthesis head***, reverse shoulder joint endoprosthesis body***, metallic reverse shoulder joint endoprosthesis cup***, humeral head endoprosthesis liner***). The presence of significant bone defects and soft tissue changes often makes shoulder arthroplasty complex primarily. Reverse shoulder arthroplasty is preferred. In the presence of total rotator cuff deficiency, the reverse endoprosthesis design allows for improved shoulder function due to the isolated action of the deltoid muscle [47-50].

Performing proximal humeral arthroplasty in pediatric patients is difficult due to limitations in available designs. The operation of choice may be the use of a vascularized fibular autograft, harvested with its proximal segment, to replace proximal humeral defects or eliminate pseudoarthrosis of the metaphyseal part in the presence of a compromised humeral head [93, 94, 95, 96, 97].

• For patients with an ununited fracture or femoral neck pseudoarthrosis, surgical treatment is recommended—hip arthroplasty (hemiarthroplasty of the hip, total hip arthroplasty, or orthopedic hip arthroplasty) to improve lower extremity function and eliminate pain syndrome [2, 50, 51-55].

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

Comments: femoral neck pseudoarthroses develop in up to 80% of cases following conservative treatment of femoral neck fractures, and in up to 40% of cases following surgical treatment (osteosynthesis), and are avascular. The low efficacy of osteosynthesis in fractures of this localization is due to the anatomical and functional features of the blood supply and the low regenerative capacity of this zone. Therefore, the recommended surgical intervention for femoral neck pseudoarthrosis is joint arthroplasty, which in this pathology falls under complex primary arthroplasty cases. The difficulties are caused by osteoporosis of the acetabulum and proximal femur, proximal migration of the femur, the development of a flexion-adduction contracture, and a large number of scars in the joint area [51-53].

The type of endoprosthesis and its method of fixation in the bone are chosen in accordance with current clinical guidelines «Proximal Femoral Fractures» [66].

Considering the high incidence of endoprosthesis head dislocation in patients with pseudoarthroses, especially long-standing ones and those following previous failed surgical treatments, dual-mobility total endoprostheses should be preferred over osteosynthesis [54-58].

3.2 Pharmacotherapy

Preoperative conservative treatment should aim to relieve pain using NSAIDs and/or paracetamol** depending on its severity, or opioid analgesics if those are ineffective, as well as preparing the patient for major surgery, which implies compensating for comorbid conditions.

Following revision surgeries for nonunions or pseudoarthroses of long bones of the lower extremities, as well as after any major orthopedic surgeries on the musculoskeletal system, the patient requires pharmacological thromboprophylaxis for venous thromboembolic events using antithrombotic agents (ATC code B01A Antithrombotic agents), as detailed in specialized guidelines [113], alongside symptomatic therapy including adequate analgesia, nutritional support, iron supplements in the presence of anemia, and systemic antibiotic therapy [104]. In addition, infusion therapy to correct circulating blood volume and electrolyte disturbances, as well as medications to treat comorbidities, may be prescribed as indicated.

Comments. Multimodal analgesia, defined as the use of various analgesic drugs and techniques targeting different mechanisms of action in the peripheral and/or central nervous system, can provide additive or synergistic effects and more effective pain relief compared to unimodal methods. Various multimodal combinations and regimens are possible for each specific situation, depending on the scope of the specific surgery and the patient's individual characteristics. Systemic therapy can be combined with local administration of local anesthetics, as well as regional or neuraxial anesthesia, especially to prevent intense pain in the early postoperative period [114].

• For patients with an ununited fracture or pseudoarthrosis in cases of fracture-related infection, a combined prolonged (at least 6 weeks) high-dose antibiotic therapy is recommended [116, 117].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

• In adult patients with an ununited fracture or pseudoarthrosis who are diagnosed with a fracture-related infection in the postoperative period, if there is positive clinical and laboratory dynamics during a course of parenteral antibiotic therapy, it is recommended to switch to oral administration of systemic antibacterial drugs with high bioavailability [118].

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

Comments. The mainstay of antibacterial therapy for implant-associated infections (IAI) is inpatient intravenous administration (lasting 7–14 days) followed by a transition to oral administration of predominantly bactericidal antibiotics with good bioavailability [119]. The issues of antibacterial therapy for fracture-related infections are detailed in the Clinical Guidelines: Implant-Associated Infections [104]. Expert consensus recommendations suggest prescribing antibiotic therapy for 6 weeks during implant removal and osteomyelitis treatment, and for 12 weeks during one- or two-stage implant exchange [119, 120]. In patients with delayed infection, the duration of the antibiotic course is individual and may continue throughout the entire fracture healing period and for 1–2 weeks after the removal of the orthopedic fixation system [119]. Bone consolidation must be regularly assessed, and the implant should be removed after fracture healing, which can significantly shorten the course of antibiotic therapy. In addition to the antibacterial drug's activity against the identified pathogen, patient-related factors must be considered: a history of drug allergies, renal and hepatic function, and the ability to take the drug orally. To prevent antibiotic-associated colitis, prescribing antidiarrheal microbial agents should be considered.

• For patients with an ununited fracture or pseudoarthrosis in cases where a fracture-related infection is detected as part of complex IAI treatment, local antimicrobial therapy is recommended to achieve effective concentrations of antibacterial drugs in the purulent focus within the bone tissue [121-123].

GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).

Comments. For any implant-associated infection in trauma and orthopedics, the standard technique is the impregnation of bone cement with antimicrobial agents to form a mantle or an antimicrobial spacer. In post-traumatic and/or postoperative osteomyelitis, bioceramics based on calcium sulfates or phosphates, or hydroxyapatite, are used in some cases. When choosing antimicrobial agents for use in bone cement, it is advisable to consider the results of preoperative microbiological analysis of the aspirate (if available) or the suspected nature of the pathogen. The list of antibiotics for addition to bone cement is presented in the Clinical Guidelines: Infections Associated with Orthopedic Implants [104].

3.3 Dietary therapy

Not indicated.

3.4 Other treatment

Comments: modern physiotherapy makes wide use of dozens of physical and natural factors: high- and low-voltage electric currents of direct and alternating directions, electric, magnetic (exposure to magnetic fields) and electromagnetic fields, ultrasonic vibrations, various types of light (exposure to visible range radiation), air and water ions, oxygen under increased pressure, medicinal substance inhalations, natural and artificial mineral waters, thermal methods of treatment using paraffin (exposure to paraffin in bone system diseases), ozokerite therapy in bone system diseases, and therapeutic mud treatment in bone system diseases. The choice of the physical factor and the method of physiotherapeutic treatment depends on the stage of reparative bone tissue regeneration, the nature of the fracture, the method of fragment fixation, the patient's ability or inability to visit the physiotherapy department, and its equipment (Level of Evidence Confidence – 2) [66-68].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Pseudoarthrosis is a complex condition that can significantly impact a person's quality of life. Understanding its causes, symptoms, diagnosis, and treatment options is essential for effective management of this condition and promoting recovery regardless of the treatment method. By following rehabilitation recommendations, one can significantly improve treatment outcomes, achieve functional improvement, and restore quality of life, allowing a return to daily activities [72].

Comments: rehabilitation is carried out by a multidisciplinary rehabilitation team (MDRT) and begins within the first 48 hours after hospital admission and surgical treatment according to individual programs, with specific goals and objectives in accordance with the method and stage of orthopedic treatment, the patient's age, and health status. Rehabilitation programs are based on the differentiated use of physiotherapeutic factors, methods, and therapeutic exercise means that address general tasks of preventing complication development and maintaining patient motor activity, as well as local tasks of preventing functional disorders in the limb and restoring its function [70-72].

Comments: The early stage of rehabilitation begins in the hospital and continues on average up to 2 weeks after surgery. The outpatient stage is carried out after the removal of immobilization in a day hospital or specialized rehabilitation centers. According to indications, in case of pronounced functional changes and due to the duration of the regeneration process, it is recommended to continue rehabilitation in specialized restorative treatment hospitals or sanatorium-resort institutions.

Indications and contraindications for prescribing certain means of medical rehabilitation are determined individually, taking into account the localization of the injury, the method of surgical fracture stabilization or conservative immobilization, as well as the patient's age, general condition, and the presence of concomitant internal organ pathology.

Comments: based on the causes of delayed consolidation—the main ones being excessive mobility in the fracture area due to inadequate immobilization and impaired blood supply in the fracture area or the limb—the rehabilitation program is primarily aimed at improving blood circulation in the limb.

During the immobilization period or the early postoperative period, the following are prescribed:

- UHF therapy (high-frequency electromagnetic field exposure (inductothermy), ultra-high-frequency electric field exposure (UHF EF)) promotes vasodilation of the circulatory system. Due to this, blood flow is activated, edema is reduced, and the intensity of pain is decreased.

- Magnetotherapy (exposure to magnetic fields) as a means of preventing fracture non-union and stimulating the formation of the callus. Under the influence of constant and alternating magnetic fields (A17.30.019), mineral metabolism in bones is accelerated, which speeds up the fusion of fragments.

- Exposure to sinusoidal modulated currents (SMC) (with the aim of improving microcirculation and tissue nutrition).

- Ultraviolet skin irradiation to activate microcirculation and saturate them with oxygen.

- Exposure to interference currents, which activate microcirculation, resulting in reduced edema and pain syndrome.

- Electrophoresis of medicinal products for bone pathology (calcium ions) of the limb. An electric field is used to deliver calcium, necessary for bone tissue formation, into the injury area.

- Manual massage of the lower extremity and/or medical massage of the upper extremity to normalize muscle tone and improve blood circulation and tissue nutrition.

- Exposure to a low-frequency pulsed electrostatic field (A17.30.038) to improve microcirculation, reduce edema and pain;

- individual therapeutic exercise sessions for injuries and diseases of the musculoskeletal system (isometric tension of regional muscles, active movements in joints free from immobilization or adjacent to the surgically fixed fracture, dynamic exercises with undamaged limbs, and breathing exercises;

- mechanotherapy on simple mechanotherapy devices for bone fractures (A19.03.003.005) and passive mechanotherapy on motorized devices (robotic mechanotherapy for bone fractures, robotic mechanotherapy for bone fractures);

- training of movement coordination and daily living skills for the upper extremities on robotic mechanotherapy devices;

- gait training with assistive devices for lower limb injuries (training the patient in self-care during movement using an assistive support).

Comments: at this stage of rehabilitation, depending on the severity of joint contractures and muscle dysfunction, the PM&R / physical therapy / physiotherapy physician draws up a rehabilitation program prescribing:

- individual therapeutic exercise sessions (therapeutic exercise for musculoskeletal disorders in children and/or therapeutic exercise for bone fractures and/or therapeutic exercise for joint diseases and injuries) for musculoskeletal injuries and diseases (dynamic exercises with weight and resistance, using objects with progressive load);

- manual massage of the lower extremity and/or medical massage of the upper extremity (and/or hardware vacuum therapy (vacuum exposure) to restore blood circulation, lymph circulation, and muscle tone;

- hydrokinesiotherapy for bone fractures;

- electrical muscle stimulation (electrical stimulation using biofeedback) for the rapid restoration of muscle tone and strength;

- application of interference currents to improve microcirculation;

- ultrasound therapy (ultrasound exposure for joint diseases), the main objective of which is to stimulate blood supply to the tissues around the joints. However, this method must be used with extreme caution if there are metal implants that may have been used for fragment reposition;

- passive mechanotherapy using motor-driven devices (robotic mechanotherapy for bone fractures and/or robotic mechanotherapy for joint diseases and injuries) to improve joint mobility;

- biofeedback training for musculoskeletal injuries and diseases (biofeedback training based on dynamographic parameters (strength) for joint diseases and injuries to coordinate upper extremity movements and master everyday skills;

- balance therapy and gait training for lower extremity injuries.

Comments: ESWT is a treatment method using acoustic (shock) waves, which, unlike sound waves, are characterized by higher energy amplitudes and short pulse duration. ESWT triggers the remodeling of damaged tissues through a stimulatory effect on fibroblasts and tenocytes, leading to the proliferation of extracellular matrix components, including collagen and glycosaminoglycans. Shock waves enhance microcirculation and angiogenesis, promoting tissue healing, and increase the expression of angiogenic factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), which leads to vessel formation and improved oxygen delivery to damaged tissues [78, 80, 81, 83].

When applied over the fracture site, ESWT induces [75-77]:

- osteoblast proliferation via osteogenic factors (vascular endothelial growth factor A (VEGF-A) and hypoxia-inducible factor 1-alpha (HIF-1α);

- regulation and stimulation of chondrogenesis and bone tissue regeneration via a mesenchymal stem cell mechanism;

- periosteal stimulation with a reduction in osteoclast activity;

- osteoblast proliferation through the regulation of nitric oxide, protein kinase B, bone morphogenetic protein, etc.

Thus, based on the studied mechanisms of action and evidence-based literature data, ESWT is a non-invasive, safe, and effective treatment method for many musculoskeletal diseases, including cases of delayed fracture union. It is a valuable and rapidly developing treatment method which, owing to ongoing research, holds great potential for improving the treatment outcomes of many musculoskeletal conditions, primarily delayed fracture union and pseudarthroses [79, 83].

5. Prevention and Dispensary Observation

Comments: prevention of infectious complications involves strict adherence to surgical technique, accurate diagnosis of contraindications to internal fixation (excluding interventions in the presence of uncontrolled local inflammation and undiagnosed systemic chronic infections, as well as laboratory-proven metal allergies), correct execution of the surgery and postoperative period, application of short-term immobilization, early active mobilization of movements in the operated joint, delayed weight-bearing on the operated extremity, strict adherence to asepsis rules, and the use of perioperative antibiotic prophylaxis. To prevent metallosis, it is recommended to use screws and plates made of a homogeneous metal and from the same instrument set. The accidental use of screws made of different metals can lead to metallosis and late suppuration due to an electrochemical conflict between the contacting elements [6, 11, 16, 24, 25].

While recognizing the importance of all the listed therapeutic measures, it must be emphasized that the most critical factor in preventing the development of delayed union remains the earliest possible diagnosis and promptly initiated treatment of bone fractures. Prevention of union disorders includes gentle handling of the soft tissues nourishing the fragments and minimizing the stripping of the periosteum from the fragments. The use of sharp drill bits and intermittent drilling—during which the working tip is cooled with antiseptic solutions and cleared of bone debris—prevents union impairment. This avoids thermal bone necrosis, which is likely to cause lysis of the burned bone channels around the screws, leading to their loosening. Errors in implant placement (insufficient reposition of articular surface fragments) lead to delayed union, and in intra-articular fractures, to arthrosis. Axial loading on the operated extremity in the early months, resulting from patient errors or non-compliance, can lead to the failure of the osteosynthesis construct and loss of fixation, impairing the union process [3, 5, 6, 11, 16, 24, 25].

The use of plaster immobilization for the entire duration of union leads to persistent contractures and is an error in most modern treatment protocols [2, 11, 16, 24, 25].

Comments: patients are advised to be monitored at the outpatient clinic (trauma center) by an orthopedic trauma surgeon until complete union is achieved and a decision is made to remove (or retain) the implant. Once union and the function of the operated segment are restored, the patient is discharged from follow-up [2, 70, 64].

6. Organization of Medical Care

Stages of medical care delivery for patients with delayed unions and non-unions (pseudarthroses) of long bones:

• primary pre-medical health care;

• primary physician-delivered health care;

• primary specialized health care;

• emergency, including specialized emergency, medical care;

• specialized, including high-tech, medical care.

Medical care for patients with delayed unions and non-unions (pseudarthroses) of long bones is provided in accordance with Order of the Russian Ministry of Health No. 901n dated November 12, 2012, “On Approval of the Procedure for Providing Medical Care to the Population in the Profile ‘Traumatology and Orthopedics’.”

Indications for inpatient hospital admission for patients with fracture non-union (pseudarthrosis)

Indications for planned hospitalization:

1. Clinically and radiologically confirmed fracture non-union (absence of union after twice the average healing time for the given anatomical location).

2. Presence of complications requiring surgical treatment:

   • Hypertrophic or atrophic non-union with extremity function impairment.

   • Infected pseudarthrosis (osteomyelitis, fistulae).

   • Bone deformity threatening the development of contractures or instability.

3. Failure of conservative treatment.

4. Need for reconstructive and plastic surgery:

Indications for emergency hospitalization:

1. Open pseudarthrosis with signs of infection.

2. Pathological fracture in the pseudarthrosis zone.

3. Acute impairment of limb blood supply or innervation due to fragment displacement.

Indications for hospital discharge:

• Postoperative criteria (in case of surgical treatment):

  1. Stable fixation of fragments confirmed radiologically.

  2. No signs of wound infection.

  3. Limb weight-bearing capacity restored (for lower limbs: ability for partial weight bearing).

  4. Pain syndrome relieved.

• In conservative management:

  1. Adequate immobilization selected.

  2. Rehabilitation plan prescribed.

  3. No indications for surgical treatment at the time of discharge.

Note: The final decision on hospitalization/discharge is made by the attending physician, taking into account the patient's individual characteristics.

7. Additional Information

To evaluate treatment outcomes in patients with delayed union and nonunions (pseudarthrosis) of long bones, questionnaires have been developed to assess (a) the functional result of treatment and (b) the patient's health-related quality of life:

• SF-36 Questionnaire – assessment of health-related quality of life in adults.

• PedsQL 4.0 Generic Core Scales – assessment of health-related quality of life in children (aged 2 to 4 years; 5 to 7 years; 8 to 12; 13 to 18 years).

These questionnaires have been translated into Russian, and studies on the validation of the translations have been published (see Appendix G).

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of medical care for patients with delayed union and nonunions (pseudarthroses) of long bones (ICD-10 codes M84.1, M84.2).

References

Appendix A1. Working Group Composition

1. Grazhdanov K.A. – Candidate of Medical Sciences, Senior Researcher, Department of Innovative Projects in Traumatology and Orthopedics, Saratov State Medical University (SSMU) Research Institute of Traumatology, Orthopedics and Neurosurgery (RIITON), Saratov, member of ASRA.

2. Zuev P.P. – Candidate of Medical Sciences, Junior Researcher, Department of Innovative Projects in Traumatology and Orthopedics, SSMU RIITON, Assistant, Department of Traumatology and Orthopedics, SSMU, Saratov, member of ASRA.

3. Ostrovsky V.V. – Doctor of Medical Sciences, Director of SSMU RIITON, Saratov.

4. Rubashkin S.A. – Candidate of Medical Sciences, Senior Researcher, Department of Innovative Projects in Traumatology and Orthopedics, SSMU RIITON, Saratov.

5. Ulyanov V.Yu. – Doctor of Medical Sciences, Deputy Director for Scientific and Innovative Activities, SSMU RIITON, Deputy Head of the Department of Innovative Technologies in Treatment and Rehabilitation Management, SSMU RIITON, Saratov.

6. Mokhovikov D.S. – Head of Traumatology and Orthopedics Department No. 4, National Ilizarov Medical Research Center for Traumatology and Orthopedics of the Russian Ministry of Health, Candidate of Medical Sciences, Trauma and Orthopedic Surgeon, member of ASRA.

7. Kolchin S.N. – Trauma and Orthopedic Surgeon, Traumatology and Orthopedics Department No. 4, National Ilizarov Medical Research Center for Traumatology and Orthopedics of the Russian Ministry of Health, Candidate of Medical Sciences, member of ASRA.

8. Belenky I.G. – Doctor of Medical Sciences, Associate Professor, I.I. Dzhanelidze St. Petersburg Research Institute of Emergency Medicine, St. Petersburg, member of ASRA.

9. Bozhkova S.A. – D.Sc. in Medicine, Professor, Vreden National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health, St. Petersburg, member ofCTOR.

10. Mayorov B.A. – Ph.D. in Medicine, Janelidze St. Petersburg Research Institute of Emergency Medicine, Pavlov University, St. Petersburg, member of ATOR.

11. Sergeev G.D. – Ph.D. in Medicine, Janelidze St. Petersburg Research Institute of Emergency Medicine, St. Petersburg, member of ATOR.

Conflict of interest: the working group members declare no conflict of interest regarding the development of these clinical guidelines.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines: traumatologists-orthopedists, surgeons, plastic surgeons, pediatric surgeons, emergency physicians, general practitioners (family physicians), feldshers.

Material collection for formulating recommendation theses (sections 2-5 of the clinical guidelines) was intended to be performed by analyzing clinical guidelines for shoulder girdle and humeral fractures prepared by foreign medical professional non-profit organizations based on evidence-based medicine principles; however, focused searches in PubMed (query: («humer*»[tiab] OR «clavic*»[tiab] OR «scapula*»[tiab]) AND «fracture*»[tiab] AND «guid*»[ti]) and Google (query: fracture guideline humerus OR clavicle OR scapula) did not yield any eligible documents. Therefore, the recommendation theses were formulated based on the expert opinion of the working group members, drawing upon scientific sources known to them.

The search for scientific information for the sections of the clinical guidelines was performed among articles in peer-reviewed scientific journals using narrow thematic queries in Russian on eLIBRARY.RU, and in English on PubMed and Google (query tracking was not performed); titles, abstracts, and full texts (if available) of the most relevant entries were reviewed; when sources of varying dates were available, priority was given to more recent publications.

The level of scientific evidence supporting the recommendation theses was evaluated according to Tables 1 and 2, and the strength of the recommendation theses was determined according to Table 3 (Appendix No. 2 to the Requirements for the Structure of Clinical Guidelines, Composition and Scientific Validity of Information Included in Clinical Guidelines, approved by Order of the Russian Ministry of Health No. 103n dated February 28, 2019).

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, rehabilitative interventions)

Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

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

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Constitution of the Russian Federation.

2. Resolution of the Supreme Soviet of the RSFSR No. 1920-1 dated November 22, 1991, "On the Declaration of Human and Civil Rights and Freedoms".

3. Criminal Code of the Russian Federation No. 63-FZ dated June 13, 1996 (as amended on July 31, 2025).

4. Criminal Procedure Code of the Russian Federation No. 174-FZ dated December 18, 2001 (as amended on July 31, 2025).

5. Federal Law No. 323-FZ dated November 21, 2011 (as amended on July 23, 2025) "On the Fundamentals of Protecting Citizens' Health in the Russian Federation".

6. Federal Law of the Russian Federation No. 4180-1 dated December 22, 1992 (as amended on May 1, 2022) "On Human Organ and/or Tissue Transplantation".

7. Federal Law of the Russian Federation No. 91-FZ dated June 20, 2000 "On Amendments to the Law of the Russian Federation 'On Human Organ and/or Tissue Transplantation'".

8. Federal Law No. 61-FZ dated April 12, 2010 (as amended on December 26, 2024) "On the Circulation of Medicines" (with rev. and add., effective March 1, 2025).

9. Federal Law No. 3-FZ dated January 8, 1998 (as amended on December 25, 2023) "On Narcotic Drugs and Psychotropic Substances".

10. Federal Law No. 152-FZ dated July 27, 2006 (as amended on February 28, 2025) "On Personal Data".

11. Order of the Russian Ministry of Health No. 901n dated November 12, 2012 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Medical Care to the Population in the Profile 'Traumatology and Orthopedics'".

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Delayed consolidation is a condition where the average time required for the healing of a fracture at a given location has passed, but clinical and radiological signs of healing are not determined. In delayed consolidation, callus formation more commonly occurs via "secondary healing" and over a longer period.

Non-union of a fracture or bone pseudarthrosis – all forms of pathological conditions accompanied by a disruption of bone integrity with the presence of abnormal mobility along the limb segment. The degree of abnormal mobility is determined by the form of the pseudarthrosis.

Treatment of these pathological conditions is almost always surgical, typically constituting major surgery. Treatment of an ununited fracture or bone pseudarthrosis is a prolonged process that generally takes longer than the consolidation of a "fresh" fracture of the corresponding localization, lasting up to several months or even over a year, and therefore requires considerable effort and patience.

Complications (impaired fracture healing, failure and displacement of the implanted hardware, inflammation, restriction of joint mobility in the injured limb) occurring in patients after surgical and conservative treatment of delayed-union and ununited fractures (pseudarthroses) of long tubular bones may lead to prolonged treatment duration and the need for inpatient hospitalization.

Signs of complications:

• pain in the operated segment, especially if appearing after a pain-free interval;

• appearance of painful mobility or crepitus in the area of the former fracture or pseudarthrosis operated on with an implant;

• decreased range of motion or pain upon movement;

• radiological findings indicating impaired consolidation or fragment displacement;

• appearance of deformity or painful induration in the operated segment;

• edema of the segment and discoloration (redness or pigmentation), pain after a pain-free interval. The most frequent causes are patient non-compliance with medical recommendations, surgical technique errors, or structural defects of the implants.

It is essential to be aware of the factors that may contribute to the development of complications:

• re-injury of the operated segment;

• overweight/obesity;

• parathyroid gland disorders;

• diabetes mellitus;

• incorrect selection of crutches, immobilization devices, braces, and plaster casts;

• systemic and local osteoporosis, including that associated with systemic diseases (major collagenoses, hormonal disorders, prolonged corticosteroid therapy, emaciation, and restrictive fad diets);

• genetic predisposition to impaired consolidation;

• sequelae of polytrauma with impaired limb function, making it difficult to adhere to the therapeutic regimen, restrictions and load dosing, and rational physical and functional therapy.

To prevent and monitor complications, it is necessary to:

• pay close attention to medical recommendations received after orthopedic surgery, especially regarding weight-bearing, immobilization periods, and the initiation and intensity of mobilization. If uncertain about the instructions, re-confirm with the operating surgeon what can and cannot be done by the patient in the postoperative period, and especially after discharge from the hospital, and in what sequence;

• thoroughly study the technique and rules for walking on crutches, the rehabilitation treatment methodology (especially the rules for safe mobilization of movements) and its phasing, i.e., transitioning from low loads and ranges of motion to their gradual increase;

• strictly adhere to the schedule of regular follow-up examinations by the traumatologist-orthopedist, including the operating surgeon (at the clinic), with control radiographic examinations prior to transitioning to the next rehabilitation period, which involves changing the loads and determining their optimal intensity;

• apply rehabilitation therapy only after coordinating its intensity and nature with the operating orthopedist (clinic department).

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

Appendix G1 SF-36 Questionnaire.

Russian title: SF-36 Questionnaire.

Original title (if any): 36-Item Short Form Health Survey (SF-36).

Source: validation publication [74], official developers' website: https://www.rand.org/health-care/surveys_tools/mos/36-item-short-form.html

Type (underline):

1. rating scale

2. index

3. questionnaire

4. other (specify): _________________________________________________

Purpose: assessment of health-related quality of life in adults [75].

Content (template): Consists of 36 questions with a single-choice answer format. The full validated Russian-language questionnaire template is available at: https://therapy.irkutsk.ru/doc/sf36.pdf

Key (interpretation): Assessment is performed across 8 health domains: Physical Functioning (PF); Role-Physical Functioning (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role-Emotional (RE); Mental Health (MH). Calculation of 2 summary measures is also possible: Mental Component Score (MCS) and Physical Component Score (PCS); the feasibility of using a Total/Global/Overall Score is being studied [31]. Each of these indicators ranges from 0 to 100 points (higher scores correspond to higher quality of life). The full Russian-language questionnaire key is available at: https://therapy.irkutsk.ru/doc/sf36a.pdf

Notes:______________________________________________________________                             

Appendix G2 PedsQL 4.0 Generic Core Scales Questionnaires.

Original title (if any): Pediatric Quality of Life Inventory Generic Core Scales (PedsQL 4.0 GCS).

Russian title: PedsQL 4.0 Generic Core Scales Questionnaires.

Original title (if any): Pediatric Quality of Life Inventory Generic Core Scales (PedsQL 4.0 GCS).

Source: validation publication [76, 77], official developer website: https://www.pedsql.org/

Type (underline):

1. rating scale

2. index

3. questionnaire

4. other (specify): _________________________________________________

Purpose: assessment of health-related quality of life in children (aged 2 to 18 years) [78, 79].

Content (template): Consists of 3 questionnaires to be completed by children in the 5–7, 8–12, and 13–18 age categories. There are also versions to be completed by parents of children aged 2 to 18 years. The full validated Russian-language template of the pediatric version of the questionnaire for the 8–12 and 13–18 age categories is available in Appendix G3 of the clinical practice guidelines "HIV Infection in Children" (ID 459), approved by the Scientific and Practical Council of the Russian Ministry of Health and approved in 2020: http://cr.rosminzdrav.ru/recomend/459

Key (interpretation): Assessment is performed across 4 health domains: physical functioning, emotional functioning, social functioning, and role functioning — school functioning. It is also possible to calculate 3 summary measures: total score across all questionnaire scales, psychosocial health summary score, and physical health summary score. Each of the 7 specified indicators ranges from 0 to 100 points (higher scores correspond to a higher quality of life). The full Russian-language key for the pediatric version of the questionnaire for age categories 8–12 and 13–18 years is available in Appendix G3 of the clinical practice guidelines "HIV Infection in Children" (ID 459), approved by the Scientific and Practical Council of the Russian Ministry of Health and approved in 2020: http://cr.rosminzdrav.ru/recomend/459

Notes:_____________________________________________________________________