**4. Risk factors in osteonecrosis**

Numerous risk factors for AVN have been described including long-term glucocorticoid treatment, diabetes, alcoholism, osteoporosis, atherosclerosis, pancreatitis, cirrhosis, hypertriglyceridemia, vasculitis, acute trauma, radiotherapy, neoplasias, air or fat embolism, barotraumas hemoglobinopathies, such as sickle cell disease and infection.

#### **4.1. Osteonecrosis and osteoporosis**

also been called post-traumatic vertebral ON [3, 5, 7], IVC [8, 9], vertebral pseudarthrosis [10],

KD occurs more frequently in the middle and in the elderly slightly predominant in males [7]. The incidence of KD in elderly patients ranges from 7 to 37%. One of the characteristic symptoms is an acute pain especially in the early stages of the disease usually without accompanying neurological symptomatology. In these cases, falls are generally conditioning factors of pain. The kyphotic deformity associated with recurrent pain of greater intensity in later stages usually corresponds to the collapse of the vertebral bodies and is usually located in the thoracolumbar region. Then neurological signs such as weakness of the lower extremities, paresthesias, as well as neuropathies that interfere with normal function of the digestive tract

Steel related the KD to insignificant trauma generally involving the 3rd thoracic vertebra and the 2nd or 3rd lumbar vertebra predominantly observed in males. He also described five stages namely *initial insult*, characterized by hyperflexion of the spine and association to the trauma of variable type and severity, in addition to normal roentgenograms. The second stage or *posttraumatic period* was manifested by mild back pain without functional limitation. The third stage, *latent interval or state of relative well-being*, was characterized by progressive disability in the following week or months of the traumatic event, not incapacitated. In this period, variability in time from 4 weeks to 1 year has been described [2, 5, 7, 11, 14–18, 20–23]. Fourth stage or *recrudescent stage*, in this the patient presents localized, persistent back pain, tenderness, and tendency to peripheral irradiation. In the last stage or *terminal stage*, the patient develops permanent kyphotic deformity with or without progressive pressure on roots or spinal cord [2]. Neurological symptoms are usually absent in the early stages of the disease and when pain occurs in the thoracolumbar region this usually corresponds to the collapse of the vertebral body. In the advanced stages, the patient develops paresthesias, lower extremity weakness, and bowel/bladder disturbance [7]. Besides, the kyphotic deformity associated with osteoporotic vertebral fracture limits the functionality and has repercussions on the quality of life of the patient. In addition, it increases the mortality and incidence of fractures in adjacent bone

Numerous risk factors for AVN have been described including long-term glucocorticoid treatment, diabetes, alcoholism, osteoporosis, atherosclerosis, pancreatitis, cirrhosis, hypertriglyceridemia, vasculitis, acute trauma, radiotherapy, neoplasias, air or fat embolism, barotraumas

delayed post-traumatic vertebral body collapse [11, 12] and nonunion of VCF [10, 13].

**3. Clinical manifestations**

22 Osteonecrosis

and bladder can develop.

structures [25, 26].

**4. Risk factors in osteonecrosis**

hemoglobinopathies, such as sickle cell disease and infection.

As we know, osteoporosis is one of the metabolic disorders associated with compression fractures of the vertebrae. This affects the quality of life of patients, who develop progressive spinal deformities that deteriorate gait and balance [27], increasing the risk of fracture [8] and mortality [28]. As mentioned, one of the mechanisms most involved in post-traumatic vertebral collapse is ischemic necrosis frequently associated with IVC in osteoporotic spine fractures [29]. According to what has been reported in the literature, the IVC sign is not pathognomonic of KD and is common to observe in unstable osteoporotic CF [30]. Two stages in the evolution of the KD have been considered, although the pathophysiological mechanisms are not known with certainty. First, after the initial trauma, the vertebrae present partial or incomplete healing with consequent weakening. In this stage, the consolidation of an osteoporotic vertebral compression fracture is characterized by an active remodeling process. This includes resorption of necrotic bone and cartilaginous tissue, endochondral bone neoformation, new vessel formation and restoration of bone continuity in the fracture line. Likewise, zones of hypertrophic trabecular bone or areas with lack of bone repair can be observed; in addition, fragments of bone, cartilage and intervertebral disc can be sequestered in areas of dense fibrous and collagen tissue [31].

The second stage of the evolution of KD involved in this reparative failure could be impaired vertebral blood flow, herniation of nucleus pulposus into the vertebral body (Schmorl's nodes), and stress conditions in weakened vertebrae [3]. As it is known, the blood supply of each vertebra depends on branches of the corresponding segmental arteries, which nourish the vertebral body, the spinal canal and the posterior third (equatorial, metaphyseal and peripheral branches) [32, 33]. It was also reported that the supply of the ventral part of the vertebral body derives from the anterior central branches of the segmental arteries, whereas the supply of the dorsal part comes from the posterior central branches [34]. This distribution anatomy has been the explanation of the frequency of IVC in the anterosuperior and anteroinferior portions of the vertebral body. Generally, the involvement of the anterior third of the collapsed vertebral body represents the vascular watershed zone related to alterations in the blood supply [7, 35].

Although the pathogenesis of KD remains unknown, in addition to the ischemic process, the motion between the fracture ends has been considered a preponderant factor. Since Hasegawa's description of the intravertebral cleft with the presence of serous fluid, surrounded by smooth fibrocartilaginous tissue and absence of lining, as well as the motion between the ends of the fracture, the development of pseudarthrosis has been consistent [36]. This radiographically supported motion in the progressive disappearance of a radiolucent gas-like area and the appearance of an area of fluid-like signal intensity on MRI has suggested that the IVC results from a migration of intradiscal gas between the ends of the osteoporotic spine fractures [6, 37]. Then, this nonunion would correspond to the persistence of the radiolucent line of the cleft and the hypointense line on MRI.

It is even reported when confirming the occlusion of the segmental artery on magnetic resonance angiography and identifying the presence of thrombi in microscopic analysis. Then it was postulated that an insult in the segmental artery could lead to AVN of the vertebral body with the consequent nonunion. It was also suggested an analogy between the deficit of the blood flow and the mechanical insufficiency of the subchondral fracture in the AVN of the femoral head and the mechanisms of osteoporotic CF [38]. Occlusion of the predominantly anterior and peripheral metaphyseal arteries seems to be observed in fragments of the fracture. Necrotic cancellous bone and hyaline cartilage endplate with fracture callus, fibrosis, fibrin deposition and hemorrhage as changes in AVN have been described [38, 39]. Some observations have been made regarding these approaches. The collapse of the basivertebral foramen located between the two pedicles in osteoporotic CF could be involved in the ischemic process of the vertebral body. This foramen allows the passage of nerve branches, basivertebral veins and arteries derived from the segmental ones [33, 40–43].

#### **4.2. Glucocorticoid treatment and osteonecrosis**

Long-term glucocorticoid therapy is a predisposing factor that induces the deposition of intramedullary fat with secondary compression of intramedullary vascularity, development of fatty microemboli and microfractures associated with osteopenia [35]. Hypertrophy and hyperplasia of fat cells in the bone marrow [44], the consequent increase in intraosseous pressure, microcirculatory occlusion by emboli and/or thrombi and decreased blood flow are important elements in the pathophysiology of induced steroid-induced ON [45]. Also, these lead to a decrease in collagen synthesis and osteoblastic activity [46]. In experimental studies in animal models, it has been demonstrated in addition to the effect of lovastatin, lipid-lowering agent, on the differentiation of cells from bone marrow into adipocytes, the preventive action or reduction of steroid-induced ON [47]. Therefore, it was proposed that lovastatin suppresses steroidinduced adipogenesis, decreases the fat cell transcription factor PPARg2 expression and favors osteoblastic differentiation, as well as *in vivo* expression of *Cabf1/Runx2 genes* [47, 48]. Then, inhibition of hypertrophy and proliferation of bone marrow fat cells and the formation of emboli by the inhibitory action of hydroxymethylglutaryl-coenzyme A reductase decreases the possibility of microvascular occlusion [49, 50].

Several studies have reported the association of steroid use and decreased bone mineral density [51–53]. In this regard, long-term methylprednisolone treatment in immature pigs was used; it was observed that blood flow was reduced in endplates and cancellous bone in 61% of the cases and showed the correlation of ON with radiographic IVC [54]. This suggested that the reduction of blood supply could be a pathophysiological factor in glucocorticoid-induced ON and that its results did not vary depending on the projection expression (g/cm<sup>2</sup> ) or volumetric bone mineral density (g/cm3 ) [54].

#### **4.3. Vertebral osteonecrosis y pancreatitis**

Few cases of vertebral intraosseous fat necrosis have been described [55, 56]. Its frequency is up to 0.8% and its main manifestations are multiple pathological fractures [56]. Pathophysiologically, the destruction of adipose tissue is a consequence of the lipolytic activity of the lipase released into the bloodstream [57]. Then, there is obstruction of the bone vascularity by drops of fat which leads to local intravascular coagulation and ON. In addition, intramedullary swelling and increased intraosseous pressure result from the release of prostaglandin E1 [58].

#### **4.4. Type 1 Gaucher disease (GD1) and vertebral osteonecrosis**

As is well known, Gaucher disease is a lysosomal storage disorder resulting from an autosomal recessive mutation in *GBA1 gene* that encodes acid β-glucosidase. Deficiency of this enzyme favors deposition of glucocerebroside in the lysosomes of mononuclear phagocytes from different organs including the skeleton [59, 60]. The main bone affections include osteopenia, fractures, and AVN [61, 62]. The clinical presentation may be silent as a spinal cord infarction due to asymptomatic obstruction of the vascularity of the bone marrow. Bone infarction is generally detected on MRI [63]. Although pathophysiological mechanisms have not been elucidated, various GBA1 genotypes associated with or without AVN have been reported [64].

Skeletal involvement in most patients with Gaucher disease is well known [59, 60, 65]. The main skeletal affections of this condition include AVN, osteopenia, and fractures [61, 62, 65]. Various authors refer to an incidence of 8–36.4% of spinal fractures in patients with GD1 [64, 66–70]. They proposed that anemia and decreased bone mineral density of the lumbar spine are strong risk factors for fractures and AVN [64].

It has been estimated that the risk of untreated AVN and GD1 is 22.8 per 1000 person-years of follow-up [71]. It has also been proposed that imiglucerase therapy reduces the presentation of AVN at 13.8 per 1000 years of follow-up [72]. The pathophysiology of AVN in GD1 is unknown, however, it is presumed to be associated with secondary spinal infarction likely to microvascular occlusion, visualized in MRI [63].

#### **4.5. HIV and vertebral osteonecrosis**

with the consequent nonunion. It was also suggested an analogy between the deficit of the blood flow and the mechanical insufficiency of the subchondral fracture in the AVN of the femoral head and the mechanisms of osteoporotic CF [38]. Occlusion of the predominantly anterior and peripheral metaphyseal arteries seems to be observed in fragments of the fracture. Necrotic cancellous bone and hyaline cartilage endplate with fracture callus, fibrosis, fibrin deposition and hemorrhage as changes in AVN have been described [38, 39]. Some observations have been made regarding these approaches. The collapse of the basivertebral foramen located between the two pedicles in osteoporotic CF could be involved in the ischemic process of the vertebral body. This foramen allows the passage of nerve branches, basi-

Long-term glucocorticoid therapy is a predisposing factor that induces the deposition of intramedullary fat with secondary compression of intramedullary vascularity, development of fatty microemboli and microfractures associated with osteopenia [35]. Hypertrophy and hyperplasia of fat cells in the bone marrow [44], the consequent increase in intraosseous pressure, microcirculatory occlusion by emboli and/or thrombi and decreased blood flow are important elements in the pathophysiology of induced steroid-induced ON [45]. Also, these lead to a decrease in collagen synthesis and osteoblastic activity [46]. In experimental studies in animal models, it has been demonstrated in addition to the effect of lovastatin, lipid-lowering agent, on the differentiation of cells from bone marrow into adipocytes, the preventive action or reduction of steroid-induced ON [47]. Therefore, it was proposed that lovastatin suppresses steroidinduced adipogenesis, decreases the fat cell transcription factor PPARg2 expression and favors osteoblastic differentiation, as well as *in vivo* expression of *Cabf1/Runx2 genes* [47, 48]. Then, inhibition of hypertrophy and proliferation of bone marrow fat cells and the formation of emboli by the inhibitory action of hydroxymethylglutaryl-coenzyme A reductase decreases the

Several studies have reported the association of steroid use and decreased bone mineral density [51–53]. In this regard, long-term methylprednisolone treatment in immature pigs was used; it was observed that blood flow was reduced in endplates and cancellous bone in 61% of the cases and showed the correlation of ON with radiographic IVC [54]. This suggested that the reduction of blood supply could be a pathophysiological factor in glucocorticoid-induced

Few cases of vertebral intraosseous fat necrosis have been described [55, 56]. Its frequency is up to 0.8% and its main manifestations are multiple pathological fractures [56]. Pathophysiologically, the destruction of adipose tissue is a consequence of the lipolytic activity of the lipase released into the bloodstream [57]. Then, there is obstruction of the bone vascularity by drops of fat which leads to local intravascular coagulation and ON. In addition, intramedullary swelling

) or volu-

ON and that its results did not vary depending on the projection expression (g/cm<sup>2</sup>

and increased intraosseous pressure result from the release of prostaglandin E1 [58].

) [54].

vertebral veins and arteries derived from the segmental ones [33, 40–43].

**4.2. Glucocorticoid treatment and osteonecrosis**

24 Osteonecrosis

possibility of microvascular occlusion [49, 50].

metric bone mineral density (g/cm3

**4.3. Vertebral osteonecrosis y pancreatitis**

HIV infection has been reported as one of the factors associated with vertebral ON. In these patients, the use of corticosteroids, abuse of alcohol and tobacco, hypercoagulable states, treatment with antiretroviral drugs, lipodystrophy, and the use of megestrol acetate or testosterone have been reported as risk factors [73–83]. It is estimated that the incidence of ON in HIVinfected patients is 0.03–0.65 cases per 100 person-years [81, 84]. In all cases reported, the participation of one or more risk factors and multifocal involvement were considered [85, 86]. Likewise, HIV-infected patients without risk factors and ON have also been reported [87].

The prevalence of osteoporotic vertebral fractures in HIV-infected patients has been increasing [88]. Likewise, the association of ON in HIV-positive individuals has been reported [89]. In the literature, only two cases of vertebral ON in HIV-infected patients and treatment with highly active antiretroviral therapy (HAART) have been reported, which presented refractory pain and developed rapid progressive kyphotic deformity [90, 91]. Drugs such as tenofovir induce increased bone remodeling and demineralization favoring bone fragility and vertebral CF [92]. Also, therapy with protease inhibitors promotes fat infiltration of the bone marrowand increase of intraosseous pressure compromising vascular irrigation [93].

#### **4.6. Sarcoidosis and vertebral osteonecrosis**

Sarcoidosis is a systemic condition in which the involvement of the musculoskeletal system occurs in 5% of patients [94–97]. Although the spinal involvement in sarcoidosis is rare, about 30 patients in the literature have been reported. A patient with sarcoidosis discarded the possibility of osteoporotic vertebral collapse due to the shape and narrowing of the intravertebral groove, the involvement of the body and the posterior elements of the vertebra and lack of evidence of new bone formation in the collapsed body [19].
