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10 Articles in Volume 13, Issue #10
Poor Adherence to Opioid Pain Management Regimens
A Practical Approach to Discontinuing NSAID Therapy Prior to a Procedure
Opioid-induced Osteoporosis: Assessing Causes and Treatments
Persistent Acute Lower Back Pain: The Importance of Psychosocial Evaluation
Research Advance Of The Year
A Day of Consulting in Rural America
Ask the Expert: Should You Test For and Treat Opioid-induced Hypogonadism?
Ask the Expert: Do NSAIDs Cause More Deaths Than Opioids?
News Briefs
Letters to the Editor

Opioid-induced Osteoporosis: Assessing Causes and Treatments

Osteoporosis is being recognized more frequently as a side effect of chronic (long-term) use of opioid medications. Screening should be considered in all patients on chronic opioid medication because treatment is much more effective when osteoporosis is detected early.

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

Altered Mental Status

Another significant confounder that may contribute to fractures in opioid users is the direct effect that opioids have on the central nervous system (mental function, sedation, dizziness). Opioid use is associated with altered mental status, which can lead to falls and subsequent fractures. Opioid- naïve patients who are started on opioids for the first time are at a particularly high risk for altered sensorium. Li et al demonstrated that acute use of opioids was associated with a much higher fracture risk than chronic use of opioids.13 In this study, opioid use for 1 to 15 days yielded a 3-fold fracture risk as compared to that seen in opioid-free patients. Surprisingly, in this study, extreme chronic use (>20 opioid prescriptions) was associated with decreased risk of fractures. This may suggest that other factors besides endocrinopathies are responsible for increased fracture risk in patients on opioids.13

For patients on chronic opioid medications, other factors may contribute to osteoporosis including the tendency to be less active, causing deconditioning, falls, and potential fractures.14


Many patients on chronic opioids tend to have other risk factors that can lead to osteopenia, including smoking, alcohol use, and comorbid illnesses requiring additional medications that predispose to bone loss. Smoking and alcohol use in particular are thought to be associated with bone loss. Alcohol use also can be associated with mental status changes—opioids further compound the effect of alcohol on the brain.15 In addition, long-term use of alcohol (>3 drinks per day) is associated with nutritional deficiencies that can accelerate opioid-associated bone loss. Many chronic conditions such as chronic obstructive pulmonary disease (COPD), obesity, inflammatory bowel disease, and hyperthyroidism are associated with bone loss. Medications that frequently are associated with decreased bone mass include corticosteroids, chemotherapeutic agents, ketoconazole, spironolactone, cimetidine, and marijuana.16


The literature on opioid-associated osteoporosis does not provide much guidance about who and when to screen. However, it has become an emerging standard in specialty pain practice to periodically test for serum testosterone levels in patients on daily opioids, particularly those who are on long-acting or intrathecal opioids. Indeed, there are published articles that suggest screening for hypogonadism in patients taking long-term morphine or morphine-equivalent medications. As noted, morphine doses over 100 mg per day have been associated with the development of hypogonadism.6 Therefore, screening of these individuals is reasonable based on the NOF Guidelines.12 These guidelines consider hypogonadism as a risk factor, although they do not consider opioids as a medication risk factor for osteoporosis, but rather a risk factor for falls, which should be considered when determining whom to screen. Screening should include bone density measurements performed every 2 years.12 (See Ask the Expert).

Testosterone replacement in male pain patients is becoming routine throughout the country and is considered by some to be the cornerstone of osteoporosis prevention in opioid-maintained pain patients.

To prevent accidental falls, clinicians need to start opioid therapy at low dosage and titrate upwards over time to insure tolerance and prevent sedation. Benzodiazepines and antidepressants should be used with caution in opioid-maintained patients because they are known factor in falls.12

How to Treat Bone-loss And Weakness

Once bone loss has occurred, little is known about the best treatment. However, there are many similarities between opioid-associated bone loss and other forms of bone loss and there are treatment overlaps as well (Table 1). One option is to stop opioid use altogether—usually through a slow taper. Although this is a tempting option, it is frequently unsuccessful due to the need for treatment of the underlying pain and the lack of other suitable alternatives. In some selected patients, other medication classes can be used, such as non-steroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, antidepressants, and acetaminophen—but a risk versus benefit analysis must be performed because some NSAIDs and acetaminophen also have been linked to a small increase in overall fracture risk.16

Non-pharmacologic methods also offer options for weaning patients off opioids. These include behavioral therapy, weight-bearing exercise, acupuncture, injection using anesthetics/corticosteroids, radiofrequency nerve ablation, and spinal cord stimulation. Vitamin Dand calcium are well known regulators of bone homeostasis and are commonly used supplements for treatment of osteoporosis. The NOF recommends that men age 50 to 70 years of age consume 1,000 mg per day of calcium and that women age 51 and older, and men age 71 and older, consume 1,200 mg per day. Taking more than the recommended amount may increase the risk of developing kidney stones, cardiovascular disease, and stroke.12 For vitamin D, the NOF recommends an intake of 800 to 1,000 international units (IU) per day.

Another option is to consider switching the class of opioids (opioid rotation). One study has focused on opioid class and bone loss.15 This study found that buprenorphine, meperidine, and propoxyphene (discontinued in US) were not associated with bone loss, whereas morphine, fentanyl, methadone, oxycodone, tramadol, and codeine were. In selected patients with opioid-related bone loss, switching to opioids that are not associated with bone loss may be a reasonable alternative.15

FDA-Approved Medications For Osteoporosis

Pharmacologic treatment of opioid- related osteoporosis usually includes bisphosphonates, calcitonin, estrogens (estrogen and/or hormone therapy), selective estrogen-receptor modulator (raloxifene), parathyroid hormone (teriparatide) and the RANKL (receptor activator of nuclear factor κ-B ligand) inhibitor denosumab (Table 2).12 The benefits of FDA-approved osteoporosis treatments mainly have been studied in women with postmenopausal osteoporosis.


The bisphosphonates include alendronate, ibandronate, risedronate, and zoledronic acid. The mechanism for these medications involves the inhibition of osteoclasts, the primary cell responsible for bone breakdown. These medications work exceptionally well and are the most commonly prescribed medications for osteoporosis treatment. The most common side effect is gastrointestinal distress.12


Calcitonin has been shown to reduce vertebral fractures but not long bone fractures. Calcitonin works by inhibiting osteoclastic bone reabsorption. The most common side effect is rhinitis due to the nasal delivery system.12

Estrogen/Hormone Therapy

Estrogens have been shown to reduce fracture risk in women but have potential cardiovascular side effects and increase the risk for breast and uterine cancer.12 These risks have limited the use of estrogen in treatment of osteo- porosis in women.12 Selective estrogen-receptor modulators (SERMs) such as raloxifene may be considered in women with osteoporosis but have not been shown to improve bone density in long bones.12 Teriparatide, a synthetic parathyroid analogue, also may be considered for treatment of osteoporosis, particularly in men and postmenopausal women. Because the safety and efficacy of teriparatide has not been demonstrated beyond 2 years of treatment, it is indicated only for use up to 2 years.12

Denosumab is a RANKL inhibitor. RANKL inhibitors act by decreasing osteoclast activity in bone. It has been shown to decrease vertebral and hip fracture risk. Denosumab has few studies of efficacy and long-term safety, so it is not recommended first line for osteoporosis treatment unless intolerance of other agents is demonstrated.12


In males with documented hypogonadism, testosterone replacement is recommended as long as no contraindications are present, such as prostate or breast cancer (Table 3).17 Although studies have not been performed in opioid-induced hypogonadism, patients with other forms of hypogonadism have shown a significant increase in bone density when receiving testosterone replacement.18-19 If testosterone replacement does not provide adequate for bone density improvement, then treatment should include the bisphosphonates, if tolerated by the patient.17

Future Considerations

Given that one of the primary mechanism by which opioids induce osteoporosis is GnRH inhibition, it seems reasonable that GnRH supplementation may be a sensible treatment option for these patients. In our research of the topic, we came across no articles offering an opinion on GnRH supplementation as treatment for opioid-induced osteoporosis. This may be a worthwhile research study in the future in an attempt to attain a superior treatment.


Millions of Americans take opioids. Long-term opioid use is associated with bone loss, which is often asymptomatic until significant osteoporosis has occurred. The bone loss seems to be due to a number of factors including the development of androgen deficiencies. The risk of osteoporosis should be considered in all patients on long-term opioids, with appropriate screening for hormone deficiencies and bone mass density testing. Patients with hormone deficiencies should be treated with those hormones that are found to be deficient as a major preventive measure for osteoporosis. Specific treatment for opioid-associated osteoporosis is not well described in the literature, but should follow the principles of other causes of osteoporosis and includes pharmacologic and non-pharmacologic modalities. Future research may consider the use of GnRH agonists to treat this condition.


Last updated on: December 9, 2013
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