Treating Osteoporotic Pain: Expert Interview

Osteoporosis affects more than 200 million people worldwide, with a higher prevalence in women compared with men.¹ In the United States, the estimated prevalence is 10.3% in adults aged 50 years and older, and an additional 43.9% of this population has been shown to have low bone mass.²

Osteoporosis is generally not painful unless a fracture occurs; the acute pain resulting from vertebral fractures often develops into a chronic pain condition via peripheral and central sensitization processes. The acute phase “is followed by a musculoskeletal chronic pain component and then by a cascade of events characterized by multiple vertebral compressions, dorsal kyphosis, decreased height, exaggerated lordosis, mechanical compression of nerve roots or spinal cord, with the induction of continuous abnormal stress on spinal muscles, facet joints and ligaments,” noted the authors of a review article published in Osteoporosis International.³

Unlike bone mass, the density of sensory nerve fibers that innervate the skeleton and transduce pain appears to remain largely intact with advancing age, resulting in a relative increase in the “density” of bone innervation. Although healthy bone depends on a balance between osteoblastic and osteoclastic activity, the latter predominates in osteoporosis. “Osteoclasts degrade bone mineral by secreting protons through the vacuolar H+-ATPase, creating an acidic microenvironment,” which activates transient potential vanilloid receptor type 1 channels, noted the authors.

These receptors “activate peripheral bone nociceptors, inducing pain and neural sensitization,” while also inducing the release of neuropeptides that promote bone degradation, including calcitonin gene-related peptide, substance P, and vasoactive intestinal peptide. “By their involvement in nociception, inflammation, angiogenesis and cellular proliferation neuropeptides contribute to the progress of painful osteoporosis,” the authors wrote.

Osteoporotic pain resulting from fractures is associated with increased disability and reduced functional capacity and self-esteem. As anti-osteoporosis drugs are typically insufficient to fully control fracture-related pain, appropriate treatment requires a multimodal approach involving both pharmacologic and nonpharmacologic strategies.

Clinical Pain Advisor interviewed Farshad M. Ahadian, MD, professor of anesthesiology and medical director of the Center for Pain Medicine at the University of California, San Diego, who offered the detailed treatment recommendations presented here.

Clinical Pain Advisor: What is generally known about pain related to osteoporotic fractures?

Dr Ahadian: Osteoporosis is a disorder of age that leads to decreased bone strength and increased risk for fractures. Bone loss in osteoporosis is asymptomatic unless it leads to bone fracture. Pain caused by osteoporotic fractures may be acute or chronic, and may involve both nociceptive and neuropathic pain mechanisms, depending on the specific anatomic findings and biomechanical changes caused by the fracture.

Care of this population is often complicated by advanced age, leading to drug intolerances and multiple comorbidities that may preclude the patient from more invasive and surgical treatment options. Careful assessment of the mechanisms of pain and the use of a multimodal, balanced approach to pain care will increase the likelihood of success and patient satisfaction while limiting risks.

Clinical Pain Advisor What are the treatment options for osteoporotic pain?

Dr Ahadian: Pharmacologic agents are usually the first line of therapy for control of pain in acute osteoporotic fractures. For mild to moderate pain, acetaminophen alone may be adequate for many patients. Nonstreoidal antiinflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors have specific efficacy for the control of bone pain.⁴ However, dosage and duration of therapy may need to be limited because of renal, gastrointestinal, and cardiovascular comorbidities to limit adverse events.

Clinicians should consider a trial of topical agents such as lidocaine and NSAIDs, as they may reduce the overall burden of pain by reducing associated myofascial pain.

Calcitonin has been shown to be effective in controlling acute pain caused by osteoporotic fractures, but not for the management of chronic bone pain.⁵ Bisphosphonates have been used for treatment of bone pain related to a variety of conditions, including osteoporotic fractures and bony metastasis. Short-term use of these agents in the acute phase may be helpful in controlling pain and reducing reliance on opioids.

Opioids may be indicated in the acute phase for patients with moderate to severe pain and where NSAIDs and selective COX-2 inhibitors are not appropriate. Our understanding of risk with opioid therapy has advanced significantly. Prescribing should begin with opioid risk assessment, to include psychosocial risk factors such as history of substance use or opioid use disorder and other psychologic and psychiatric comorbidities as well as physiologic comorbidities such as pulmonary, cardiovascular, renal, or hepatic disease and sleep apnea. 

Higher doses of opioids, use of long-acting opioid preparations, longer duration of opioid therapy, and specific opioids such as oxycodone and methadone have all been associated with increased opioid-related morbidity and mortality. Furthermore, there is concerning evidence of increased risk for osteoporosis and fractures resulting from direct and indirect effects on bone metabolism, as well as opioid-induced hypogonadism.^6,7 Therefore, whenever possible, the use of time-contingent, short-acting agents is preferred, and opioid therapy should be discontinued once pain levels have declined into the mild to moderate range. 

Tramadol and tapentadol are alternative analgesic agents to consider. Tramadol has mild selective serotonin reuptake inhibitor and serotonin and noerpinephrine reuptake inhibitor (SNRI) activity and weak opioid receptor activity. Tapentadol combines SNRI activity with opioid receptor agonism. Both agents have a good safety profile and a better tolerability profile than opioids in this population, and are suitable for moderate pain levels.

Clinicians should also consider a trial of alternative therapies such as acupuncture. In recent years, there has been as significant increase in published acupuncture clinical trials indicating efficacy for a variety of conditions.⁸ Acupuncture is well-tolerated, and in addition to reduction in pain, it may improve well-being, sleep, and mood. It may also be used to reduce reliance on opioids.

Although gabapentinoids and SNRIs are commonly used for a variety of pain conditions, caution is advised when considering these agents in patients with osteoporotic compression fractures. Recent evidence suggests that both these classes of drugs may lead to significant loss of bone mass and density, and increased risk for falls and fractures, whereas evidence is lacking for efficacy of these agents for this indication.^9,10

Although pharmacologic agents can provide rapid access to analgesia, minimally invasive interventional pain therapies may be more likely to provide significant life-changing improvements in pain, function, and quality of life for patients suffering from osteoporotic fractures. Osteoporotic compression fractures have a complex mechanism of pain that includes nociceptive and neuropathic pain and central sensitization, which may be responsible for persistence of the pain into the chronic phase. 

Interventional therapies may help not only by rapid interruption of nociceptive pain pathways but also by playing a role in preventing the facilitated pain state. Examples include the use of:

• epidural steroid injections, selective dorsal root ganglion blocks, and blockade of the rami communicans and the sympathetic chain for vertebral compression fractures;
• facet nerve block and radiofrequency treatment for facet arthropathy related to biomechanical changes after vertebral compression fractures;
•  trigger point injections for management of secondary myofascial pain component;
• suprascapular nerve block for fractures involving the proximal humerus; and
• neural blockade and radiofrequency treatment of the articular branches of the femoral and obturator nerves for fractures involving the hip or proximal femur.

More definitive therapy of poorly or nonhealing fractures using vertebral augmentation techniques may be indicated. Consider early referral to a fellowship-trained pain specialist to determine whether these minimally invasive techniques may be indicated.

Clinical Pain Advisor: In summary, what are the top takeaways for our clinicians?

Dr Ahadian: Targeted assessment is critical to include pain location and severity, pain mechanisms, and opioid risk stratification

Use a stepwise approach to analgesic therapy as follows:

• nonopioids and NSAIDs as first-line therapy;
• consider trial of topical agents;
• consider tramadol or tapentadol for moderate pain;
• use time-contingent, short-acting opioids and limited duration of opioid therapy, when possible, to reduce opioid-related mortality and morbidity;
• discontinue opioids as soon as the patient’s condition allows;
• consider medical acupuncture; and
• consider early consultation with pain specialist.

Clinical Pain Advisor: What should be the focus of future research in this area?

Dr Ahadian: Additional research is needed regarding the use of monoclonal antibodies for osteoporotic pain, the inhibition of bone resorption, early identification of at-risk populations, and preventive strategies throughout adolescence and adulthood. 

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References

1. Vellucci R, Mattia C, Celidonio L, Mediati RD. Implications of analgesics use in osteoporotic-related pain treatment: focus on opioids. Clin Cases Miner Bone Metab. 2016;13(2):89-92.
2. Wright NC, Looker AC, Saag KG, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014;29(11):2520-2526.
3. Vellucci R, Terenzi R, Kanis JA, et al. Understanding osteoporotic pain and its pharmacological treatment [published online April 4, 2018]. Osteoporos Int. doi: 10.1007/s00198-018-4476-y
4. Knopp-Sihota JA, Newburn-Cook CV, Homik J, Cummings GG, Voaklander D. Calcitonin for treating acute and chronic pain of recent and remote osteoporotic vertebral compression fractures: a systematic review and meta-analysis. Osteoporos Int. 2012;23(1):17-38.
5. Bannuru RR, Dasi UR, McAlindon TE. Reassessing the role of acetaminophen in osteoarthritis: systematic review and meta-analysis. Osteoarthr Cartil. 2010;18(Suppl 2):S250.
6. Coluzzi F, Pergolizzi J, Raffa RB, Mattia C. The unsolved case of “bone-impairing analgesics”: the endocrine effects of opioids on bone metabolism. Ther Clin Risk Manag. 2015;11:515-523.
7. Aloisi AM, Aurilio C, Bachiocco V, et al. Endocrine consequences of opioid therapy. Psychoneuroendocrinology. 2009;34(Suppl 1):S162-S168.
8. Schiller J, Korallus C, Bethge M, et al. Effects of acupuncture on quality of life and pain in patients with osteoporosis-a pilot randomized controlled trial. Arch Osteoporos. 2016;11(1):34.
9. Kanda J, Izumo N, Kobayashi Y, et al. Effects of the antiepileptic drugs phenytoin, gabapentin, and levetiracetam on bone strength, bonemass, and bone turnover in rats. Biol Pharm Bull. 2017;40(11):1934-1940.
10. Bruyère O, Reginster JY. Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome. Endocrine. 2015;48(1):65-68.