Opioids and bone density

The unsolved case of “bone-impairing analgesics”: the endocrine effects of opioids on bone metabolism – Ther Clin Risk Manag –  2015 Mar  – free full-text PMC article

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

The onset of intolerable side effects often leads to the decision to reduce drug dosage, raising the risk of inadequate analgesia, leading to the establishment of a dangerous “vicious cycle”

Different studies have shown that both men and women chronically treated with opioids are at an increased risk for a reduction in BMD. Preclinical studies have shown that some opioids have a lower osteoporotic effect than others; however, it is still unclear which opioids are less likely to cause endocrine dysfunction and posses the best profile for minimizing the negative effects on bone metabolism

Similarly, more studies are needed to identify which patients need to be screened, what length of time is needed to develop endocrine dysfunction after starting opioids, and if these effects are reversible after stopping opioid therapy

It is reasonable to think that analgesics that have a lower contribution of MOR activity to the overall analgesic effect could represent the best choice in the delicate balance between analgesic efficacy and adverse effects.

If further studies confirm this hypothesis, the choice of analgesic drug for chronic pain management should also take into consideration this particular endocrinological–metabolic aspect, especially in predisposed, frail, and elderly patients.

But here’s a more recent study finding exactly the opposite:

Opioid receptor agonists may favorably affect bone mechanical properties in rats with estrogen deficiency-induced osteoporosis – Naunyn Schmiedebergs Arch Pharmacol – 2016 Nov – free full-text PMC article

The results of epidemiological, clinical, and in vivo and in vitro experimental studies on the effect of opioid analgesics on bone are inconsistent.

The aim of the present study was to investigate the effect of morphine (an agonist of opioid receptors), buprenorphine (a partial μ opioid receptor agonist and κ opioid receptor antagonist), and naloxone (an antagonist of opioid receptors) on the skeletal system of female rats in vivo.

The experiments were carried out on 3-month-old Wistar rats, divided into two groups:

nonovariectomized (intact; NOVX) rats and

ovariectomized (OVX) rats

Morphine and buprenorphine beneficially affected also the skeletal system of NOVX rats, but the effects were much weaker than those in OVX rats

Naloxone generally did not affect the rat skeletal system.

The results confirmed the role of opioid receptors in the regulation of bone remodeling processes and demonstrated, in experimental conditions, that the use of opioid analgesics at moderate doses may exert beneficial effects on the skeletal system, especially in estrogen deficiency.


The effects of drugs acting through opioid receptors on the skeletal system, investigated in the present study, did NOT confirm the damaging action of opioid analgesics, which might have been expected based on the literature.

In fact, beneficial effects of morphine and buprenorphine in rats with estrogen deficiency were observed. A similar, though weaker, effects were present in rats with normal estrogen levels.

Administration of an opioid receptor antagonist, naloxone, did not exert opposite effects to those induced by the investigated opioid analgesics.

The only unfavorable effect of morphine on the skeletal system in the present study was the inhibition of the longitudinal growth of the tibia and femur, concurrently with the decrease in body mass gain.

Consistently, a reduction in the number of cells in the proliferation zone of the growth plate (and the growth plate width) under the influence of morphine was demonstrated in young rats.

Also, a restriction of fetal growth often occurs during pregnancy in opioid-dependent women, although numerous studies have demonstrated the stimulatory effect of opioids on the secretion of growth hormone

Neither buprenorphine, a partial μ receptor agonist and κ receptor antagonist, nor naloxone, an opioid receptor antagonist, affected the longitudinal bone growth.

Morphine and buprenorphine counteracted the development of osteoporotic changes in the skeletal system of OVX rats.

Estrogen deficiency in rats, similarly as in postmenopausal women, leads to increased bone remodeling processes with the predominance of resorption over formation, and cancellous bone is more affected than compact bone

This was confirmed in the present study; both bone formation and bone resorption were increased, and bone mineralization was impaired in OVX rats.

After administration of the opioid agonists to OVX rats, bone turnover rate slowed down, as demonstrated by significant reduction of bone formation and bone resorption markers

Also, bone mineralization was improved

These activities led to the increase in the strength of the tibial metaphysis (cancellous bone)

The effects of opioid agonists on the skeletal system of NOVX rats were limited to the improvement of bone mineralization (morphine and buprenorphine) and mechanical properties of cancellous bone (morphine).

(There are two types of bone tissue: cortical bone and cancellous bone: The tissues are biologically identical; the difference is in how the microstructure is arranged.

Cortical bone, synonymous with compact bone forms the extremely hard exterior of bones.

Cancellous bone is synonymous with spongy bone. Cancellous bone has a higher surface area to mass ratio than cortical bone because it is less dense. This makes it softer, and weaker but more flexible.)

Although long-term use of opioids in humans leads to the development of hypogonadism, administration of morphine, buprenorphine, and naloxone in the present study did not affect the serum estradiol level and uterus mass/body mass ratio.

(Hypogonadism means diminished functional activity of the gonads—the testes in males or the ovaries in females—that may result in diminished sex hormonebiosynthesis.)

In fact, the skeletal effects of morphine and buprenorphine in OVX rats were similar to those induced by estradiol supplementation in our previous studies

Results of the present study are at variance with the widely held view that opioid analgesics unfavorably affect the skeletal system in humans, based on most of previous reports

There are epidemiological data indicating the decreased BMD in patients treated with opioids in relation to nontreated controls

Interestingly, the decreased BMD during methadone maintenance therapy was observed in male patients only

However, those studies did not determine the changes in the skeletal system, and the data were rather not adjusted for other factors, like the treated diseases and poor general health status

Other studies demonstrated that the use of opioid analgesics is associated with an increased risk of fractures, to which the increased risk of falls may contribute

Nevertheless, results of the present study are consistent with recently published reports on the possible favorable opioid effects on the skeletal system in women

It was also demonstrated in a population-based nested case-control study that morphine tends to exert the protective action on the skeletal system of female patients with cancer.

The use of morphine in patients treated with bisphosphonates significantly reduced the risk of osteoporosis (compared with patients on bisphosphonates only)

Results of these studies indicate on the possibility of favorable direct opioid effects on bones.

Previous experimental studies demonstrated rather bone-damaging effects of opioid receptor agonists.

The inhibition of fracture healing by morphine was demonstrated in rats; this effect, however, was associated with inhibition of callus resorption

The mechanism of the beneficial effect of morphine and buprenorphine observed in the present study may be associated with their direct effects on opioid receptors in bone cells.

The significance of the study is that it for the first time reports on the favorable effects of opioid receptor agonists (morphine and buprenorphine), used in the therapeutic dose range, on the skeletal system in female rats, especially in conditions of estrogen deficiency.

Based on the results of the present study, it seems likely that opioids also in humans may not only not damage the skeletal system but also exert some direct favorable effects, which are counteracted by indirect detrimental ones. This seems to be important in the light of numerous, both reasonable and unfounded, concerns over the use of the opioid analgesics in the long-term therapy of pain.

In conclusion, results of the present study confirmed the role of opioid receptors in the regulation of bone remodeling processes and demonstrated, in experimental conditions, that the use of opioid analgesics at moderate doses may have beneficial effects on the skeletal system, especially in estrogen deficiency.


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