Opioid-induced Osteoporosis: Assessing Causes and Treatments
According to the Institute of Medicine, chronic pain affects approximately 100 million American adults—more than the total affected by heart disease, cancer, and diabetes combined.1 The use of opioids for treatment of chronic pain has increased substantially over the past decade—nearly doubling from 11.3% to 19.6% between 2000 and 2010.2 Estimates suggest that millions of patients take opioids daily to control pain.3,4
Side effects of opioid treatment are fairly common and can affect the gastrointestinal (constipation, nausea), central nervous, cardiovascular, and genitourinary systems. One side effect that is often overlooked but increasing in frequency is the effect opioids have on the musculoskeletal system. More specifically, opioids are being recognized as a risk factor for bone loss in patients who take them chronically. Bone loss initially is a silent process, making it less likely that physicians will consider it in evaluating patients on opioids. Bone loss over time, however, can cause a significant increase in the risk of osteoporosis and fractures, increasing the cost of care for patients and affecting quality of life.
In this article, we will explore the causes of opioid-associated osteoporosis, screening recommendations, and potential treatment options.
What Causes Opioid-associated Osteoporosis?
Patients on long-term opioids appear to be at higher risk of developing osteopenia and osteoporosis. Duarte et al found that 50% of patients receiving intrathecal opioids demonstrated osteopenia (defined as T score between -1.0 and -2.5 SD), with more than 20% diagnosed with osteoporosis (T score </ -2.5 SD).5 Other sources report the incidence of osteoporosis in hypogonadal men to be as high as 50%.6
Gender has shown to have a varying effect on the risk for developing opioid-induced osteopenia/osteoporosis. In one study, men and women both develop premature osteoporosis that was thought to be caused by chronic opioid use.7 Women demonstrated bone densities in the osteoporotic range prior to age 40 at a much higher rate than expected.7 Men in the study frequently had testosterone levels <50 ng/dL (in the male castrate range), which was associated with osteopenia.7 However, in a study of patients in a methadone maintenance program, only men demonstrated lower bone mineral density scores. In the study, by Grey et al, men had a 10% lower bone density as compared to controls, whereas women had bone densities approaching those of the age-matched general population.8 The 10% lower bone mineral density is associated with a 2-fold increase in the relative risk of fractures in this population. Further studies will be needed to determine the exact role gender has on opioid-associated osteoporosis, given the 2 conflicting studies.
The exact mechanism is not fully known, but it appears to be multifactorial. The main contributing factors seem to be the development of endocrinopathy, direct osteoblast inhibition, mental status changes, and associated comorbities.
One of the leading causes for the bone density changes seen in patients on opioids seems to be endocrinopathies (Figure 1). Normally the hypothalamus secretes gonadotropin-releasing hormone (GnRH), which acts upon the anterior pituitary, releasing luteinizing hormone (LH) and follicle stimulating hormone (FSH). The anterior pituitary, along with growth hormone (GH), prolactin, thyroid-stimulating hormone (TSH), adrenalcorticotrophic hormone (ACTH), LH, and FSH, has an altered response to GnRH.6 These hormones have a direct effect on the production of sex hormones in the ovaries or testes, particularly testosterone.
In patients on chronic opioids, it is speculated that there is both central and peripheral inhibition of this process. Centrally, opioids are thought to inhibit the GnRH release from the hypothalamus by binding µ receptors.5 Multiple studies have shown that opioids inhibit GnRH release and testosterone production, referred to as opioid-induced androgen deficiency (OPIAD).
One manifestation of OPIAD is the development of hypogonadism. Both sexes are affected. Symptoms in males include delayed ejaculation and erectile dysfunction.5,6,9 Women may experience amenorrhea or oligomenorrhea.9,10 Hypogonadism has been proposed to be a major risk factor for the development of osteoporosis.
The enzyme 5α-reductase (5αR) has a critical role in androgen and glucocorticoid action. Peripherally, morphine has been shown to alter 5αR type 1 and/or P450 aromatase mRNA expression. This leads to the breakdown of testosterone and conversion to estradiol.9 Ceccarelli et al found that opioids increase the aromatase activity in animal models, which again leads to testosterone breakdown.10 Opioids also are thought to decrease the release of dehydroepiandrosterone (DHEA) from the adrenal glands, which can contribute to bone loss.5
Direct Osteoblast Inhibition
Another peripheral effect that opioids may exert on bone density relates to osteoblast function. It has been theorized that osteoblast function is inhibited through binding of opioids to µ receptors on osteoblasts. Inhibition of osteoblasts causes decreased synthesis of new bone, which can cause a decrease in bone density.6 In many of these studies, osteocalcin is used as a biomarker for osteoblast activity. It has been shown to be decreased in patients taking chronic opioids.6 Another study that further strengthens the concern for a peripheral inhibition of osteoblast activity was done by Fortin et al.11 In the study, 81 men on both acute to long-term opioid therapy had blood samples and bone scans performed. The researchers found a discrepancy between the percentage of men with hypogonadism (27%) and the percentage of with osteopenia/osteoporosis (44%), suggesting that monitoring for total testosterone levels is not a reliable method to determine the risk for developing opioid-associated osteoporosis.
According to the National Osteporosis Foundation (NOF), one potential factor could be the binding of osteoblast receptors causing decreased osteocalcin levels and lower bone density.12