5.1 Introduction

Osteoporosis, trauma, or neoplasm can all lead to vertebral compression fractures (VCFs). The osteoporotic compression fracture is the most commonly encountered type of fracture and the spectrum of symptoms vary widely from being asymptomatic to having excruciating pain. Nonsurgical management is the traditional first-line management for VCFs. The goals of nonsurgical management are pain control, early mobilization, prevention of deformity, and functional restoration. In spite of the nonsurgical management of VCFs being fairly common, there are relatively little data on the clinical outcomes of nonoperative management of osteoporotic VCF that have been reported. ^{1 – 3} Additionally, the studies related to the cost-effectiveness of nonsurgical management have also been sparse. In a retrospective, propensity score-matched study of vertebroplasty, kyphoplasty, and nonsurgical management for the treatment of VCFs in 2,740 patients, vertebroplasty and kyphoplasty were identified to be significantly costlier at 1-year follow-up, but at 2- and 4-year follow-ups, no significant difference in cost was found. ⁴ Moreover, the American Academy of Orthopaedic Surgeons determined that the strength of recommendation of the opioids/analgesics for patients who have VCFs is inconclusive due to a lack of data. ¹ In practice, however, the medical management with or without bracing is usually recommended as the initial conventional treatment of VCFs. ² Although medications are often used with other therapies for the treatment of back pain, they remain the mainstay in the management of moderate to severe fracture pain.

VCFs usually manifest with nociceptive pain. However, when there is concomitant foraminal stenosis, severe spinal canal stenosis, or tumor invasion, they may present with accompanying neuropathic pain. Neuropathic pain is a direct consequence of a lesion or a compressive irritation affecting the nervous system. ⁵ It is not easy to treat and the information available from randomized controlled trials upon which to base treatment in this matter is scarce. The management decisions may therefore be based on the individual physician’s perspectives and experience with this condition. The medications to manage pain include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics (including narcotics and tramadol), muscle relaxants, transdermal lidocaine, and adjuvant agents used to relieve neuropathic pain. ⁶ Although the acute pain due to VCF is generally tolerable or gone within 6 to 12 weeks, it is recommended that the pharmacological management be started with acetaminophen and/or NSAIDs. If pain does not decrease with the first-line medications, opioids can then be used (▶Table 5.1). Finally, VCFs are more frequently found in elderly patients, and physicians should be aware of the pharmacological characteristics of these medications along with the possible adverse effects associated with the them in this particular patient population.

5.2 Nonsteroidal Anti-Inflammatory Drugs

NSAIDs are the most commonly prescribed medications for the treatment of pain. They have antipyretic, anti-inflammatory, and analgesic effects; the latter two explain their use in patients needing treatment for pain. The mechanism of action of NSAIDs is the inhibition of the prostaglandin synthesis through the inhibition of the cyclooxygenase (COX) enzymes (COX-1 and COX-2), which cause anti-inflammatory and analgesic effects. The COX-2 enzyme can be induced in some stressful conditions, such as nerve injury. Several organs such as the central nervous system and the kidney express COX-1 constitutively. ⁷ NSAIDs that inhibit both COX-1 and COX-2 include aspirin, indomethacin, sulindac, diclofenac, ibuprofen, naproxen, and piroxicam. Those that selectively inhibit COX-2 include celecoxib, etoricoxib, and nimesulide. ⁷ Although few studies have been published on the use of NSAIDs in patients with VCFs, there is some low-quality evidence that demonstrates immediate- and short-term effects of NSAID on reducing the pain of VCFs. ³ Additionally, in a systematic review of 65 randomized controlled trials of NSAIDs in different types of back pain, NSAIDs were more effective than placebo and acetaminophen. However, there was strong evidence that there were no differences between the effects of various types of NSAIDs including COX-2 NSAIDs. ⁸ Additionally, in a systematic review of 13 randomized controlled trials of NSAIDs in chronic low back pain, authors identified no difference in efficacy between different NSAID types. ⁹

NSAIDs have a variety of side effects on various organ systems including the cardiovascular system (cardiovascular thrombosis, myocardial infarction, and stroke), the gastrointestinal tract (hemorrhagic gastric erosion and gastric ulcer), and the kidney (renal insufficiency, sodium and water retention, hypertension, and edema). The risk factors for NSAID-induced gastrointestinal complications include advanced age, history of ulcer, concomitant use of corticosteroids, high doses of NSAIDs, concomitant anticoagulants, serious systemic disorder, smoking, alcohol consumption, and concomitant infection with Helicobacter pylori. ¹⁰ The risk of renal toxicity increases with chronic NSAID use, multiple NSAID use, dehydration, volume depletion, congestive heart failure, vascular disease, hyperreninemia, shock, sepsis, systemic lupus erythematosus, hepatic disease, sodium depletion, nephrotic syndrome, diuresis, concomitant drug therapy, and an age of 60 years or older. ¹¹

Pharmacologically, COX-1 is involved in the formation of cytoprotective prostanoids and constitutively expressed in platelets and gastrointestinal tracts. Therefore, inhibition of COX-1 increases the risk of gastrointestinal bleeding. Gastric bleeding from preexisting gastric ulcers may also occur due to NSAID suppression of platelet aggregation. ¹² Although the exact mechanism is not fully understood, video capsule endoscopy has found that NSAID-induced enteropathy occurs in the small intestine as well as the large intestine. ¹³ Moreover, the discovery of COX enzyme, COX-1, and COX-2 led to the production of selective COX-2 inhibitors. Compared with nonselective COX inhibitors, the incidence and complications associated with gastrointestinal tract ulcers are reduced. In a comparative study, the risk of gastrointestinal adverse events was lower in patients treated with a COX-2 selective NSAID (celecoxib) than in those receiving a nonselective NSAID (diclofenac) with omeprazole. ¹⁴ Celecoxib was also associated with significantly fewer small bowel mucosal breaks than ibuprofen plus omeprazole. ^{15 , 16} The preference for COX-2 selective agents to reduce gastrointestinal tract complications, however, has likely given rise to increased cardiovascular side effects. The worrisome complications discovered by various studies resulted in the withdrawal of two of three COX-2 selective agents (rofecoxib and valdecoxib). Only celecoxib remains in the market with warnings regarding its cardiovascular profile.

The mechanism for the increase in cardiovascular risks is believed to result from an imbalance between pro- and antithrombotic prostaglandin. Thromboxane A2 is a platelet activator and vasoconstrictor, whereas prostacyclin (PGI2) is a platelet inhibitor and vasodilator. Platelet activity is maintained by the balance between thromboxane A2 effects on platelets and PGI2 effects on endothelium. Aspirin and nonselective NSAIDs inhibit both COX-1 and COX-2 and decrease both thromboxane A2 and PGI2. Conversely, COX-2 selective NSAIDs reduce PGI2 synthesis without affecting thromboxane A2 synthesis. ^{17 , 18} The antithrombotic unbalance may thereby cause the increased cardiovascular risk. Nonetheless, the Food and Drug Administration (FDA) announced labeled changes for all NSAIDs, both COX-2 selective and nonselective, that may have a similar cardiovascular risk. Consequently, patients without cardiovascular risk factors and low gastrointestinal tract risk can receive a monotherapy of an NSAID. However, patients with low cardiovascular risk without prophylactic aspirin but who are at high gastrointestinal tract risk should receive COX-2 selective NSAID or a traditional NSAID plus a proton-pump inhibitor. ¹⁹

NSAIDs may also result in deterioration of renal function and renal failure. The mechanism of renal dysfunction is a decreased renal prostaglandin production, which leads to a reduction in renal blood flow and medullary ischemia. ²⁰ The renal profile of NSAIDs is related to sodium retention and glomerular filtration rate changes. All NSAIDs have been associated with hypertension and edema, but most of these side effects improve with discontinuation of therapy. ¹¹