Spinal Compression Fracture

                                            Dr. KS Dhillon

Introduction

Vertebral compression fractures of the spine occur as a result of an axial and flexion load with resultant biomechanical failure of the bone. Compression fractures compromise the anterior column of the spine, resulting in compromise to the anterior half of the vertebral body and the anterior longitudinal ligament. This leads to a wedge-shaped deformity. 

Compression fractures do not involve the posterior half of the vertebral body, the posterior osseous components, and the posterior ligamentous complex. Compression fractures are usually stable and do not require surgery. These fractures do have a potential for deformity progression.

Etiology

The most common etiology of compression fractures is osteoporosis. These fractures are the most common fragility fractures. Compression fractures demonstrate a bimodal distribution with younger patients sustaining these injuries secondary to high energy mechanisms such as fall from a height, MVA, etc. and older patients with osteoporosis develop fractures from minor or no trauma. 

The spinal column can be divided into three columns: (1) anterior column (anterior longitudinal ligament, anterior annulus, the anterior portion of the vertebral body, (2) middle column (posterior vertebral body, posterior annulus, and posterior longitudinal ligament), and (3) the posterior column (ligamentum flavum, neural arch, facets, posterior ligamentous complex).  When two of these three columns are compromised, instability of the spine results for which surgery may be required. Compression fractures only involve the anterior column and no instability results. 

Epidemiology

Spinal compression fractures are the most common fragility fractures reported in the literature.  In the USA approximately 1- to 1.5 million compression fractures occur annually. It is estimated that 25% of women 50 years of age and older have at least one compression fracture [1]. It has been estimated that 40% to 50% of patients over age 80 years have sustained a compression fracture either acutely or discovered incidentally during clinical workup for some other condition [2].

Sixty to seventy-five percent of the fractures occur at the thoracolumbar junction (the segment from T12 to L2). Thirty percent of the fractures occur at the L2 to L5 region.

In younger patients, about 50% of the spine fractures occur due to motor vehicle accidents and another 25% occur due to falls.

Studies show that about 30% of compression fractures in the elderly occur while the patient is in bed.  With an increase in the aging population, the population at risk of sustaining low energy fragility fractures will continue to increase.  The number of patients aging and having a diagnosis of osteoporosis is projected to rise in the future [1]. Population studies show that the annual incidence of compression fracture is 10.7 per 1000 women and 5.7 per 1000 men.

Pathophysiology

During a fall or trauma, there are rotational and axial flexion/extension forces applied to the spine. The axial force which exceeds forces tolerable by the vertebral body leads to a compression fracture. More severe forces will lead to a burst fracture. The kyphotic deformity resulting from the compression fracture can alter the biomechanics of the spine leading to additional stresses on other spine levels. This altered biomechanics can cause more fractures and progressive spine deformity, especially in the osteoporotic spine. 

Clinical Presentation

More than two-thirds of patients with compression fractures are asymptomatic, and the diagnosis is made incidentally [3]. Symptomatic patients may present with back pain. Radiographs most commonly show a compression fracture between T8 and L4 [4]. Patients with an acute fracture often complain of abrupt onset of pain with position changes, coughing, sneezing, or lifting objects [5]. Physical examination may be normal. Sometimes examination may demonstrate kyphosis and midline spine tenderness [5]. Once the patient has been stabilized, an evaluation of the neurologic function of the arms, legs, bladder, and bowels should be carried out. Chronic compression fractures may present with loss of height in addition to kyphosis. Complications of compression fractures include bone loss, muscle weakness, pressure sores, ileus, urinary retention, impaired respiratory function, venous thromboembolism, and spinal cord compression [5].

The differential diagnosis includes musculoskeletal pain, multiple myeloma, metastatic disease, hyperparathyroidism, osteomalacia, primary bone neoplasms, infiltrative neoplasms, metastatic neoplasms, hematologic disease, and osteomyelitis.

Evaluation

Evaluation of patients with suspected back injury includes anterior-posterior (AP) and lateral radiographs of the injured area. Following trauma x rays should be taken with the patient supine. Once the brace has been applied standing x rays can be taken.

A CT scan should be done to obtain more details, especially to look for retropulsion of bone fragments. If posterior column injury is suspect and not seen on CT, an MRI will be needed to look for disruption of the posterior ligamentous complex. An MRI will also help to rule out metastasis.

If there is 30 degrees of traumatic kyphosis and a 50% vertebral body height loss then the fracture is considered as unstable. The presence of neurologic deficit necessitates an MRI for additional evaluation.

Dual-energy x-ray absorptiometry should be carried out after the diagnosis of compression fracture to measure the degree and severity of osteoporosis. 

If secondary osteoporosis is suspected in a young patient or in a person with symptoms of hypercalcemia or anemia, laboratory evaluation should be carried out. This would include a complete blood count, liver function test,  erythrocyte sedimentation rate, thyroid-stimulating hormone, parathyroid hormone, 25-hydroxyvitamin D, and C-reactive protein levels [6]. Blood cultures are required if infection is suspected. If myeloma is suspected, serum and urine protein electrophoresis should be performed. There is a high prevalence of low testosterone levels in young men with osteoporosis and low-trauma fractures, and measurement of the testosterone level should be considered in these patients [7].

Treatment

The goals of treatment of compression fractures include pain relief, restoration of function, and prevention of future fractures [8,9]. 

Treatment of compression fractures should begin with discussion of patient goals and risks, as well as benefits of conservative care vs. percutaneous vertebral augmentation. Patients wishing to have conservative treatment will have more than a 50% chance of sufficient pain relief, most of which occurs within three months [10]. A study by Lee et al [10] of 259 patients with compression fracture showed that those patients who had pain relief and reduced disability with three weeks of conservative therapy had a 95% chance of maintaining these improvements for up to 12 months.

Conservative Treatment

In the conservative treatment of compression fractures, early mobility should be encouraged as soon as possible. If pain is very severe, bed rest is recommended as part of initial management. Prolonged bed rest can lead to loss of bone mass and muscle strength, pressure sores, and deep venous thrombosis [11]. 

1. Pain control

Following initial evaluation and diagnosis of a vertebral compression fracture, therapy is aimed at pain control so that early mobilization becomes possible and prolonged bed-rest can be avoided.

Acute pain control can be achieved with nonsteroidal anti-inflammatory drugs (NSAIDs), narcotic pain medication, muscle relaxants, neuropathic pain agents, local analgesic patch, nerve blocks, and transcutaneous nerve stimulation units [12,13]. NSAIDs are usually first-line drugs for back pain since they do not have sedating effects. NSAIDs can produce gastric toxicity and can increase risk of cardiac events for patients with hypertension and coronary artery disease [14].

Opioids and muscle relaxants can provide strong pain relief when NSAIDs are inadequate but opioids have significant sedative effects as well as the risk of dependency. Their use needs to be carefully balanced in geriatric patients [13].

2. Physical therapy

Physical therapy helps with early mobilization in the acute phase and in the long term helps to prevent further injuries. The exercises are carried out to strengthen the patient’s supportive axial musculature, particularly the spinal extensors. Training is provided to improve the patient’s proprioceptive reflexes which will improve posture and ambulation and decrease the likelihood of future falls.

The erector spinae muscles play a crucial role in maintaining normal posture by balancing the biomechanical tendency of the spine to fall forward. This function also reduces mechanical stress on the

vertebral bodies. Strengthening the spinal extensor muscles will improve lumbar lordosis and posture [15]. This will also reduce acute fracture pain as well as chronic back pain associated with kyphotic deformity of the spine. These exercises are important since axial musculature decreases in strength with age, particularly among women who are most at risk for vertebral fracture. 

Both exercise selection and intensity should be tailored towards the individual patient to avoid over-stressing the spine and causing new injury. 

In a study by Sinaki and Mikkelsen [16] of postmenopausal osteoporotic women undergoing exercise rehabilitation, there was an 89% rate of further vertebral fracture associated with abdominal flexion training compared to only 16% with back extension exercises.

Similarly exercises aimed at increasing spinal flexibility, particularly spinal flexion, can actually reduce some of the protective mechanisms against back pain [17].

Exercises should focus on strengthening back extension and can include weighted or unweighted prone position extension exercises and isometric contraction of the paraspinal muscles [18,19,20]. 

There are several other trials that have demonstrated similar efficacy of physical therapy programs in managing painful compression fractures [21,22,23]. 

3. Bracing

Bracing is often used for symptomatic management of vertebral fractures. However, it is usually used in the treatment of burst fractures rather than compression fractures.

A prospective randomized trial by Pfeifer et al [24] on the 6-month use of a thoracolumbar orthosis (TLO) for osteoporotic compression fractures found improvement in trunk muscle strength, posture, and body height amongst the treatment group, leading to a better quality of life and ability to perform activities of daily living (ADL). The spinal orthosis maintains neutral spinal alignment and limits flexion, thereby reducing axial loading on the fractured vertebra. Furthermore, the brace allows for less fatigue of the paraspinal musculature as well as muscle spasm relief [25].

Several types of braces are available. The type of brace to use will depend on the location and severity of the fracture. 

Fractures of the thoracic spine are treated with a TLO such as the Jewitt, cruciform anterior spinal hyperextension, and Taylor brace. Braces that extend to the sacrum are termed thoracolumbar sacral orthosis. Lumbosacral orthosis are also available for lumbar fractures. 

Some of these rigid braces are uncomfortable to wear and that may decrease compliance. There is a risk for skin breakdown if the brace edges are not carefully padded. Furthermore, a brace that is too restrictive may impede the patient’s respiration.

Prolonged periods of bracing can lead to deconditioning and atrophy of the trunk and paraspinal muscles. Most authors have now moved away from recommending rigid braces and moved towards light-weight, soft braces, except in cases of severe deformity.

4. Preventative medicine

Besides acute pain control, medical therapy should aim to improve bone quality to reduce the risk of future fractures. Agents for treating osteoporosis such as bisphosphonates, selective estrogen receptor modulators, recombinant parathyroid hormone, and calcitonin should be administered. These agents act through either antiresorptive or osteogenic mechanisms [13].

The bisphosphonate alendronate (Alendronic acid) is the first-line medication given since it has a favorable safety profile and efficacy in reducing fracture risk [26].

Hormone replacement therapy can be an option for younger women who are postmenopausal [13].

Calcium and vitamin D are insufficient in reducing fracture risk but they can be used as supplements for deficient patients. Typically a 2-year treatment period is needed before improvement of bone mineral density is detected [13].

Several medications for osteoporosis treatment also play a role in acute pain relief [27]. Multiple randomized controlled trials have found that calcitonin provides pain relief for acute compression fractures [28].

Bisphosphonates have also been found to provide pain relief [29]. Patients treated with teriparatide (recombinant parathyroid hormone) show decreased back pain, when compared with patients treated with placebo, alendronate or hormone replacement therapy [30,31].

5. Nerve Root Blocks. 

Lumbar 2 nerve blocks can be used for temporary pain reduction in patients with compression fractures. The AAOS, however, gives a weak recommendation for the use of L2 nerve blocks [32]. The nerve blocks can give some pain relief for about 2 weeks to 1 month. Epidural injections have also been used for pain relief [33]. Physicians should counsel patients with compression fractures to weigh the benefits of temporary pain relief against the risks of the procedure.

Surgical treatment

Though there is no standard time for appropriate conservative management.  Patients should have pain relief by about 6 weeks. When patients continue to have unremitting pain or there is fracture progression on follow-up x-rays, surgical treatment should be considered. Surgical treatment usually involves a vertebral augmentation procedure. Vertebral augmentation procedure involves minimally invasive percutaneous vertebroplasty or kyphoplasty. 

Patients eligible for surgery should have significant back pain and tenderness in the fracture area that increases with axial loading. Furthermore, the fracture should be within the subacute phase before it is healed. Vertebroplasty or kyphoplasty cannot be carried out in patients with completely collapsed vertebral bodies (vertebra plana). 

Patients with fractures through the posterior wall of the vertebrae cannot undergo these procedures because there is a risk of cement extrusion into the spinal canal. Bony retropulsion with neurologic compromise is an absolute contraindication as this may worsen with the injection of cement. In such cases, an open surgical decompression and fixation may be more appropriate. Surgery is also contraindicated in the presence of active osteomyelitis of the fracture site and allergy to kyphoplasty cement.

Vertebroplasty and kyphoplasty

Vertebroplasty is performed by transpedicular insertion of a cannulated trocar into the fracture under fluoroscopically guidance and injection of radiopaque cement. The aim is to provide structural support to the compromised trabecular bone and restore the lost vertebral height. Usually, a bipedicular approach using two trocars is done for more even cement distribution. 

In the upper thoracic spine, where the pedicles can be very small, an extrapedicular approach may need to be used with trochar insertion between the medial rib head and lateral edge of the pedicle. The trocar is advanced into the collapsed vertebral body and steps are taken to avoid medial or lateral breaches. 

In performing kyphoplasty an additional step is involved prior to cement injection. Following the insertion of the trocar an inflatable balloon tamp is threaded into the fracture and expanded. This leads to compaction of the cancellous bone and expansion of the cavity for cement injection. This helps to restore the vertebral body height. Once the inflation cavity has been created, radiopaque cement is injected in incremental amounts. It is important to make sure that the cavity is adequately filled and no cement retropulsion into the spinal canal occurs. The aim is to provide structural support to the compromised trabecular bone and restore lost vertebral height. 

Potential complications of surgery

Usually, vertebral augmentation is performed as an outpatient procedure. There is pain relief within 24 hours. The overall complication rates for osteoporotic compression fractures is low at about 4% but increase for oncologic fractures. Symptomatic complications are less than 10% [34, 35,36].

The incidence of cement extravasation into the spinal canal or neuroforamen is between 0.4% to 4% [37,38]. Cement extravasation is often asymptomatic or transient. It can result in painful radiculopathy and weakness. 

If extravasation affects the spinal cord or conus medullaris, it can cause paraparesis and this constitutes an emergency and surgical decompression would be required. 

Cement can also extravasate into the paraspinal musculature, which usually produces no symptoms. In extremely rare instances the cement may enter the venous system and result in embolic phenomenon [38,39] or stroke [40].

Treatment outcomes

There have been a large number of trials that have examined the efficacy of vertebral augmentation compared to optimal medical management. Despite this, there has in the past been a significant controversy. More studies in the recent past have shed some light on this controversy.

Overall, there are a greater number of studies on vertebroplasty than kyphoplasty given its longer history. McGirt et al [38] published a review in 2009 of all the studies of vertebral augmentation outcomes over a 20-year period. The review included 74 studies (including one level I) of vertebroplasty for osteoporotic compression fractures, 35 kyphoplasty studies for osteoporotic fractures, and 18 studies for tumor-related fractures, which were all level IV studies. They found level I evidence that vertebroplasty provides superior pain control over medical management in the first 2 weeks. The study showed level II–III evidence that within the first 3 months there are superior outcomes in analgesic use, disability, and general health. Finally, there was level II–III evidence that by 2 years there is a similar level of pain control and physical function.

As for kyphoplasty, there was level II–III evidence of improvement in daily activity, physical function, and pain control at 6 months, compared to medical management.

For tumor-related fractures, there was insufficient evidence for comparison.

Since this review, there have been other randomized trials that have mostly shown improved pain control and physical function with vertebroplasty in the short term [41,42] but diminished or no difference with medical management at 1-year follow-up [42,43].

There was a subsequent larger randomized controlled trial that enrolled 202 patients. The authors did find sustained, significant differences at 1-year follow-up with continued improved pain relief for the vertebroplasty group [44].

In 2009, two double-blind randomized controlled trials were published in the New England Journal of Medicine that received significant publicity. These were studies by Buchbinder et al [45] and by Kallmes et al [46]. The studies involved comparisons between vertebroplasty and sham procedure groups. 

The authors of both studies reported no difference in pain control or function between the groups at follow-up. They were of the opinion that the benefits of vertebroplasty in prior trials were secondary to a procedural placebo effect [47,48].

These two studies were the subject of criticism, focusing on their low enrollment numbers (78 and 131 patients), low volume, infrequent rate of vertebroplasty performed at the centers over a long time interval, inadequate volume of cement injection, lack of clear inclusion criteria specifying patients with mechanical axial back pain [49,50].

Clark et al [51] in 2016 published a study that showed better pain relief after vertebroplasty compared with sham treatment, as measured by a score of less than 4 on a visual analogue scale at 14 days, improved quality of life, and 30% greater preservation of vertebral body height.

Firanescu et al [52] published a study in 2018 involving 180 patients and their study showed that in patients with acute osteoporotic compression fractures of the vertebral body who have persistent severe local back pain, percutaneous vertebroplasty performed at a mean of 43 days after onset of symptoms did not result in greater pain relief than a sham procedure during 12 months’ follow-up.

Conclusion

The patient’s quality of life is significantly affected by vertebral fractures and there is a high socioeconomic cost. Diagnostic studies include plain x rays, CT scans, and bone density workup with DEXA imaging. 

Conservative management is usually attempted for up to 6 weeks. Medical therapy is aimed at pain control, early mobilization with the assistance of bracing and rehabilitation, and improving the bone quality to prevent a future fracture.

If the patients remain refractory to conservative treatment or the fracture worsens on subsequent imaging, surgery may be indicated although there remains some doubts about the efficacy of vertebroplasty and kyphoplasty. Although evidence for their efficacy in oncologic fractures is limited, there are several studies that have shown at least short-term efficacy in improving pain and physical function for the more common osteoporotic fractures. These varied treatment modalities do allow for the acute and long-term management for patients with compression fractures of the vertebrae.

Reference

1. Savage JW, Schroeder GD, Anderson PA. Vertebroplasty and kyphoplasty for the treatment of osteoporotic vertebral compression fractures. J Am Acad Orthop Surg. 2014 Oct;22(10):653-64.
2. Kim HJ, Park S, Park SH, Park J, Chang BS, Lee CK, Yeom JS. Prevalence of Frailty in Patients with Osteoporotic Vertebral Compression Fracture and Its Association with Numbers of Fractures. Yonsei Med J. 2018 Mar;59(2):317-324.
3. Fink HA, Milavetz DL, Palermo L, et al.; Fracture Intervention Trial Research Group. What proportion of incident radiographic vertebral deformities is clinically diagnosed and vice versa? J Bone Miner Res. 2005;20(7):1216–1222.
4. Patel U, Skingle S, Campbell GA, Crisp AJ, Boyle IT. Clinical profile of acute vertebral compression fractures in osteoporosis. Br J Rheumatol. 1991;30(6):418–421.
5. Longo UG, Loppini M, Denaro L, Maffulli N, Denaro V. Osteoporotic vertebral fractures: current concepts of conservative care. Br Med Bull. 2012;102:171–189.
6. Cosman F, de Beur SJ, LeBoff MS, et al.; National Osteoporosis Foundation. Clinician's guide to prevention and treatment of osteoporosis [published correction appears in Osteoporosis Int. 2015;26(7):2045–2047]. Osteoporos Int. 2014;25(10):2359–2381.
7. U.S. Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, Md.: U.S. Department of Health and Human Services, Office of the Surgeon General; 2004:1–404.
8. Longo UG, Loppini M, Denaro L, Maffulli N, Denaro V. Osteoporotic vertebral fractures: current concepts of conservative care. Br Med Bull. 2012;102:171–189.
9. Prather H, Hunt D, Watson JO, Gilula LA. Conservative care for patients with osteoporotic vertebral compression fractures. Phys Med Rehabil Clin N Am. 2007;18(3):577–591, xi.
10. Lee HM, Park SY, Lee SH, Suh SW, Hong JY. Comparative analysis of clinical outcomes in patients with osteoporotic vertebral compression fractures (OVCFs): conservative treatment versus balloon kyphoplasty. Spine J. 2012;12(11):998–1005.
11. Barr JD, Jensen ME, Hirsch JA, et al. Position statement on percutaneous vertebral augmentation: a consensus statement developed by the Society of Interventional Radiology (SIR), American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS), American College of Radiology (ACR), American Society of Neuroradiology (ASNR), American Society of Spine Radiology (ASSR), Canadian Interventional Radiology Association (CIRA), and the Society of NeuroInterventional Surgery (SNIS). J Vasc Interv Radiol. 2014;25(2):171–181.
12. Ensrud KE, Schousboe JT. Clinical practice. Vertebral fractures. N Engl J Med. 2011;364(17):1634–1642.
13. Francis RM, Baillie SP, Chuck AJ, et al. Acute and long-term management of patients with vertebral fractures. QJM. 2004; 97(2):63–74.
14. Bavry AA, Khaliq A, Gong Y, Handberg EM, Cooper-Dehoff RM, Pepine CJ. Harmful effects of NSAIDs among patients with hypertension and coronary artery disease. Am J Med. 2011;124(7):614–620.
15. Hongo M, Miyakoshi N, Shimada Y, Sinaki M. Association of spinal curve deformity and back extensor strength in elderly women with osteoporosis in Japan and the United States. Osteoporos Int. 2012; 23(3):1029–1034.
16. Sinaki M, Mikkelsen BA. Postmenopausal spinal osteoporosis: flexion versus extension exercises. Arch Phys Med Rehabil. 1984; 65(10):593–596.
17. Sinaki M. Yoga spinal flexion positions and vertebral compression fracture in osteopenia or osteoporosis of spine: case series. Pain Pract. 2013;13(1):68–75.
18. Sinaki M. Critical appraisal of physical rehabilitation measures after osteoporotic vertebral fracture. Osteoporos Int. 2003; 14(9):773–779.
19. Sinaki M. The role of physical activity in bone health: a new hypothesis to reduce risk of vertebral fracture. Phys Med Rehabil Clin N Am. 2007; 18(3):593–608, xi–xii.
20. Sinaki M, Itoi E, Wahner HW, et al. Stronger back muscles reduce the incidence of vertebral fractures: a prospective 10 year follow-up of postmenopausal women. Bone. 2002;30(6):836–841.
21. Malmros B, Mortensen L, Jensen MB, Charles P. Positive effects of physiotherapy on chronic pain and performance in osteoporosis. Osteoporos Int. 1998;8(3):215–221.
22. Bennell KL, Matthews B, Greig A, et al. Effects of an exercise and manual therapy program on physical impairments, function and quality-of-life in people with osteoporotic vertebral fracture: a randomised, single-blind controlled pilot trial. BMC Musculoskelet Disord. 2010;11:36.
23. Papaioannou A, Adachi JD, Winegard K, et al. Efficacy of home-based exercise for improving quality of life among elderly women with symptomatic osteoporosis-related vertebral fractures. Osteoporos Int. 2003;14(8):677–682.
24. Pfeifer M, Begerow B, Minne HW. Effects of a new spinal orthosis on posture, trunk strength, and quality of life in women with postmenopausal osteoporosis: a randomized trial. Am J Phys Med Rehabil. 2004;83(3):177–186.
25. Longo UG, Loppini M, Denaro L, Maffulli N, Denaro V. Conservative management of patients with an osteoporotic vertebral fracture: a review of the literature. J Bone Joint Surg Br. 2012; 94(2):152–157.
26. Ensrud KE, Schousboe JT. Clinical practice. Vertebral fractures. N Engl J Med. 2011;364(17):1634–1642.
27. Longo UG, Loppini M, Denaro L, Maffulli N, Denaro V. Conservative management of patients with an osteoporotic vertebral fracture: a review of the literature. J Bone Joint Surg Br. 2012; 94(2):152–157.
28. Knopp JA, Diner BM, Blitz M, Lyritis GP, Rowe BH. Calcitonin for treating acute pain of osteoporotic vertebral compression fractures: a systematic review of randomized, controlled trials. Osteoporos Int. 2005;16(10):1281–1290.
29. Rovetta G, Maggiani G, Molfetta L, Monteforte P. One-month follow-up of patients treated by intravenous clodronate for acute pain induced by osteoporotic vertebral fracture. Drugs Exp Clin Res. 2001; 27(2):77–81.
30. Nevitt MC, Chen P, Kiel DP, et al. Reduction in the risk of developing back pain persists at least 30 months after discontinuation of teriparatide treatment: a meta-analysis. Osteoporos Int. 2006;17(11):1630–1637.
31. Nevitt MC, Chen P, Dore RK, et al. Reduced risk of back pain following teriparatide treatment: a meta-analysis. Osteoporos Int. 2006;17(2):273–280.
32. Esses SI, McGuire R, Jenkins J, et al. The treatment of symptomatic osteoporotic spinal compression fractures. J Am Acad Orthop Surg. 2011;19(3):176–182.
33. Prather H, Hunt D, Watson JO, Gilula LA. Conservative care for patients with osteoporotic vertebral compression fractures. Phys Med Rehabil Clin N Am. 2007;18(3):577–591, xi.
34. McGirt MJ, Parker SL, Wolinsky JP, Witham TF, Bydon A, Gokaslan ZL. Vertebroplasty and kyphoplasty for the treatment of vertebral compression fractures: an evidenced-based review of the literature. Spine J. 2009;9(6):501–508.
35. Lin WC, Cheng TT, Lee YC, et al. New vertebral osteoporotic compression fractures after percutaneous vertebroplasty: retrospective analysis of risk factors. J Vasc Interv Radiol. 2008;19(2 Pt 1): 225–231.
36. Taylor RS, Fritzell P, Taylor RJ. Balloon kyphoplasty in the management of vertebral compression fractures: an updated systematic review and meta-analysis. Eur Spine J. 2007; 16(8):1085–1100.
37. Mukherjee S, Lee Y-P. Current Concepts in the Management of Vertebral Compression Fractures. Operative Techniques in Orthopaedics. 2011; 21(3):251–260.
38. McGirt MJ, Parker SL, Wolinsky JP, Witham TF, Bydon A, Gokaslan ZL. Vertebroplasty and kyphoplasty for the treatment of vertebral compression fractures: an evidenced-based review of the literature. Spine J. 2009;9(6):501–508.
39. Gangi A, Guth S, Imbert JP, Marin H, Dietemann JL. Percutaneous vertebroplasty: indications, technique, and results. Radiographics. 2003;23(2):e10.
40. Savage JW, Schroeder GD, Anderson PA. Vertebroplasty and kyphoplasty for the treatment of osteoporotic vertebral compression fractures. J Am Acad Orthop Surg. 2014 Oct;22(10):653-64.
41. Voormolen MH, Mali WP, Lohle PN, et al. Percutaneous vertebroplasty compared with optimal pain medication treatment: short-term clinical outcome of patients with subacute or chronic painful osteoporotic vertebral compression fractures. The VERTOS study. AJNR Am J Neuroradiol. 2007;28(3):555–560.
42. Wardlaw D, Cummings SR, Van Meirhaeghe J, et al. Efficacy and safety of balloon kyphoplasty compared with non-surgical care for vertebral compression fracture (FREE): a randomised controlled trial. Lancet. 2009;373(9668):1016–1024. 
43. Rousing R, Hansen KL, Andersen MO, Jespersen SM, Thomsen K, Lauritsen JM. Twelve-months follow-up in forty-nine patients with acute/semiacute osteoporotic vertebral fractures treated conservatively or with percutaneous vertebroplasty: a clinical randomized study. Spine (Phila Pa 1976). 2010;35(5):478–482.
44. Klazen CA, Lohle PN, de Vries J, et al. Vertebroplasty versus conservative treatment in acute osteoporotic vertebral compression fractures (Vertos II): an open-label randomised trial. Lancet. 2010; 376(9746):1085–1092.
45. Buchbinder R, Osborne RH, Ebeling PR, et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N Engl J Med. 2009;361(6):557–568.
46. Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med. 2009; 361(6):569–579.
47. Kallmes D, Buchbinder R, Jarvik J, et al. Response to “randomized vertebroplasty trials: bad news or sham news?”. AJNR Am J Neuroradiol. 2009;30(10):1809–1810.
48. Miller FG, Kallmes DF, Buchbinder R. Vertebroplasty and the placebo response. Radiology. 2011;259(3):621–625.
49. Aebi M. Vertebroplasty: about sense and nonsense of uncontrolled “controlled randomized prospective trials”. Eur Spine J. 2009; 18(9):1247–1248.
50. Noonan P. Randomized vertebroplasty trials: bad news or sham news? AJNR Am J Neuroradiol. 2009;30(10):1808–1809.
51. Clark W, Bird P, Gonski P, et al. Safety and efficacy of vertebroplasty for acute painful osteoporotic fractures (VAPOUR): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2016;388:1408-16. doi:10.1016/S0140-6736(16)31341-1 pmid:27544377.
52. Firanescu C E, de Vries J, Lodder P, Venmans A, Schoemaker M C, Smeet A J et al. Vertebroplasty versus sham procedure for painful acute osteoporotic vertebral compression fractures (VERTOS IV): randomised sham controlled clinical trial BMJ 2018; 361 :k1551 doi:10.1136/bmj.k1551.