Opioids have been shown to be associated with an increased risk of fracture. The purpose of this paper is to review recent research into the effects of opioids on bone formation and bone healing in animal models and in human studies.
Most opioids, such as morphine and fentanyl, negatively affected bone remodeling and bone healing in animal models. Conversely, remifentanil has been recently shown to promote in vitro osteoblast differentiation and to inhibit differentiation and maturation of osteoclasts, therefore reducing bone resorption. According to the possible negative role of opioids in bone healing, opioid antagonists have been shown to enhance bone mineralization, suggesting a possible therapeutic role in the future for osteoporosis. Other neuropeptides, such as the vasoactive intestinal peptide (VIP) and the neuropeptide Y (NPY), have been proved to promote osteogenesis. The increased risk of fractures among opioid users may be related to their central nervous system side effects or to the reduced bone density, partly due to their endocrine effects, and partly to their direct activity on bone cells. Clinical data strongly suggested a potential negative effect of opioids in bone healing. The risk of nonunion fracture is significantly increased in opioid users, and bone mass density was reduced in patients under long-term opioid treatment. The direct effects of opioids on bone remodeling appears evident from these reports. Not all opioids have the same potential for negatively impacting bone healing. Opioid antagonists may increase bone density and could represent a possible future treatment for low bone mass density pathologies. However, further trials are warranted to clarify the clinical relevance of these emerging findings from animal studies.

BACKGROUND: Opioids are an effective treatment for chronic non-malignant pain (CNP). Long-term use risks and side effects such as opioid-induced androgen deficiency (OPIAD) exist. This could be measured by saliva testosterone (Sal-T).
OBJECTIVE: To evaluate OPIAD in long-term opioid use in CNP patients.
METHODS: A cross-sectional study included CNP male outpatients under opioid treatment. Total-Testosterone (Total-T), Free-Testosterone (Free-T), Bio-Testosterone (Bio-T) and Sal-T were measured. Correlations were calculated by Spearman\'s rho (SPSS 20).
RESULTS: From 2012 to 2014, 134 from 249 (54%) consecutive male outpatients reported erectile dysfunction (ED), 37% of them related to opioids and 19% evidenced OPIAD. A total of 120 subjects (94 cases and 26 matched-controls) were included. A significantly lower luteinizing hormone, Total-T and Free-T were found, as well as, a significant correlation between Sal-T and Total-T (r = 0.234, p = 0.039), Bio-T (r = 0.241, p = 0.039), IIEF (r = 0.363, p = 0.003) and HAD-anxiety (r = -0.414, p = 0.012) in OPIAD patients. Sal-T levels were significantly lower in patients with severe-moderate ED versus mild ED (p = 0.045) and in patients with severe ED versus moderate-mild ED (p = 0.036).
CONCLUSIONS: These data demonstrate the high prevalence of ED in long-term use of opioids, part of this is associated to OPIAD, which can be tested by Sal-T as a non-invasive approach.

OBJECTIVE: Millions of patients continue to require opioid analgesics for control of moderate to severe chronic pain, which is a disease that affects more Americans than cancer, heart disease, and diabetes combined. Common opioid adverse effects include constipation, sedation, and nausea. A lesser-known sequelae is opioid induced androgen deficiency (OPIAD). The objective of this review was to better characterize the effects of opioids on the endocrine system.
METHODS: Published data were evaluated to identify links between opioid use and hypogonadism, as well as to describe proposed physiological mechanisms.
RESULTS: Chronic opioid use may predispose to hypogonadism through alteration of the hypothalamic-pituitary-gonadal axis as well as the hypothalamic-pituitary-adrenal-axis. The resulting hypogonadism and hypotestosteronism may contribute to impaired sexual function, decreased libido, infertility, and osteoporosis- none of which may be clinically recognized as opioid related.
CONCLUSIONS: OPIAD is a recognized consequence of long-term opioid therapy. Patients initiated or maintained on opioids should be queried about symptoms that might suggest hypogonadism including irregular menses, reduced libido, depression, fatigue, and hot flashes or night sweats. Some clinicians recommend assessment of baseline testosterone levels prior to initiating therapy. Additional data appear necessary to formulate guidelines regarding the diagnosis and management of OPIAD. Options include, rotating, reducing the dose or type, or cessation of opioid therapy or adding hormonal supplementation in the form of androgen replacement therapy. There are multiple formulations of testosterone available for replacement therapy, which is usually guided by laboratory measurements.

The current literature describes the possible risks for bone fracture in chronic analgesics users. There are three main hypotheses that could explain the increased risk of fracture associated with central analgesics, such as opioids: 1) the increased risk of falls caused by central nervous system effects, including sedation and dizziness; 2) reduced bone mass density caused by the direct opioid effect on osteoblasts; and 3) chronic opioid-induced hypogonadism. The impact of opioids varies by sex and among the type of opioid used (less, for example, for tapentadol and buprenorphine). Opioid-associated androgen deficiency is correlated with an increased risk of osteoporosis; thus, despite that standards have not been established for monitoring and treating opioid-induced hypogonadism or hypoadrenalism, all patients chronically taking opioids (particularly at doses ≥100 mg morphine daily) should be monitored for the early detection of hormonal impairment and low bone mass density.

BACKGROUND: Opioids can suppress testosterone in men, which can lead to extensive morbidity. Identifying risk factors for androgen deficiency in men using daily opioids could improve monitoring and safety.
METHODS: In a retrospective cohort study, we used Kaiser Permanente Northern California databases to identify men on stable doses of opioids. These subjects had no diagnoses of cancer or endocrine disorders except treated primary hypothyroidism. Subjects were divided into those using long-acting opioids and short-acting opioids. Total testosterone was measured in blood drawn in the morning while the subjects were on their regular dose of opioid. The association between opioid duration of action and androgen deficiency, controlling for dose, body mass index, age, diabetes, hyperlipidemia, and hypertension, was assessed using logistic regression.
RESULTS: The study included 1585 men. Men on long-acting opioids were more likely to be androgen deficient than men on short-acting opioids (57% vs 35%, P < 0.001; odds ratio [OR] 3.39; 95% confidence interval [CI], 2.39-4.77). As dose increased, the odds of androgen deficiency increased; however, dose was more strongly associated with androgen deficiency in men on short-acting opioids (OR 1.16; 95% CI, 1.09-1.23, for each 10-mg increase in dose) than in men on long-acting opioids (OR 1.01; 95% CI, 1.01-1.02).
CONCLUSIONS: Use of long-acting opioids is a key risk factor in the development of androgen deficiency. Dose was significantly associated with androgen deficiency, but more so for men on short-acting than on long-acting opioids.