Commentary on Grey et al. (2011): Does methadone maintenance therapy adversely affect bone mass?


Osteoporosis is associated with increased fracture risk. In addition to severe consequences for the patients' wellbeing, it also has important economic consequences. A hip fracture, for instance, is associated with a two-thirds possibility of discharge to a facility other than the patient's home. While discharge to home is associated with a mean survival of more than 4 years, discharge to a nursing home is associated with a mean survival of only 1.5 years, and additional costs roughly estimated at $95.000 (€68.000) [1].

Grey et al. have performed a long-needed study on subjects in a methadone maintenance programme, reported in this issue [2]. They found that men, but not women, had decreased bone mineral density. In addition, two-fifths of the men showed biochemical evidence of low total testosterone levels. These findings are important, as they can serve to focus the attention of the physicians caring for these subjects on two issues: nutrition and hypogonadism.

These two factors are among the most important causes of osteoporosis. In the minds of the lay public osteoporosis is associated mainly with frail bent-over older women, but the impact of a fracture can be devastating in a variety of different groups. A group that has received little attention in this regard is individuals with drug addiction. During periods where drug-seeking behaviour overrides all other life activities, it is no surprise that nutrition falls behind. Once drug addiction has been overcome, the concern for osteoporosis tends to take a back seat to other more pressing health issues such as infections. While physicians may discuss calcium intake and the possibility of osteoporosis with women by virtue of the unhealthy life-styles they have experienced, this is not likely to occur in discussions with young men, because osteoporosis has been off the radar screen in this group. In one study, subjects were evaluated before and 4 years after starting methadone maintenance. While both men and women did not consume enough calcium before starting methadone maintenance, only men failed to consume enough calcium to meet their dietary requirements after 4 years of methadone use, while women had normalized their intake [3]. The issue of adequate intake is relevant, because bone accrual lasts up to the age of 30 years [4], and adequate calcium and 25(OH) vitamin D intake is required for maintaining bone health throughout adult life [5–7]. Thus, suboptimal intake of calcium and vitamin D may play a role, but it cannot be stated definitively whether it is the reason why men in the study of Grey et al. had lower bone mineral density measurements.

Adding to the complexity of such an analysis is that methadone itself can be associated with hypogonadism [8], the symptoms of which are vague in men and range from erectile dysfunction and decreased libido to less specific symptoms such as decreased energy [9]. The insidious onset of these symptoms, which may only be recognized by the patients as a continuation of symptoms present during periods of drug abuse, make diagnosis difficult. Furthermore, measured levels of total testosterone may be misleading in a variety of patients, such as obese individuals. Therefore, estimates of male hypogonadism in the general population are up to 10-fold higher than the number of recognized cases [10]. Hypogonadism in women is much easier to diagnose because of the development of menstrual irregularities. Furthermore, the need for contraception in women often results in the use of oral contraceptives that contain oestrogen, and thus protect from hypogonadism-associated osteoporosis. In the cohort examined by Grey et al., almost two-fifths of the men had low levels of testosterone that presumably were only detected because of the participation of the subjects in the study. It should be noted that the cohort studied by Grey et al. was receiving methadone doses in the high range, which are more likely to be associated with hypogonadism [11]. In older men the levels of testosterone show a trend downwards, already beginning at age 40. Because of the large range of supposedly normal values for testosterone, it is conceivable that a person who experiences a drop from a high value to a low normal value may in fact be hypogonadal, despite a testosterone level that is still in the normal range [12,13]. Lastly, in the osteoporotic fractures in men study (MrOS) subjects with testosterone levels in the lowest quartile had a hazard ratio for the development of fracture of almost 1.5 compared to those in the higher three quartiles [14]. This effect was much stronger when sex hormone-binding globulin was taken into account, a variable for which contradictory data exist as to whether it changes at all in subjects receiving methadone maintenance [15]. If, indeed, it is increased, as proposed by another group [16], then the increase in sex hormone-binding globulin will push the level of free and bioavailable testosterone down, leading physicians to overestimate their levels. Based on these data, it seems reasonable to assume that hypogonadism contributed to decreased bone mass in subjects receiving methadone in the study by Grey et al.

In summary, the work by Grey et al. should lead physicians caring for such patients to consider two issues: counselling regarding calcium and vitamin D intake, especially in men, and determining gonadal function by asking women about menstrual irregularities and men about the non-specific symptoms associated with hypogondadism, and complementing these with determining total testosterone levels and sex hormone-binding globulin. It would be worthwhile to determine longitudinally in a large group of addicted subjects how bone turnover, bone density and fracture risk change as they transition to methadone maintenance therapy, which is a challenging task indeed. Until then many questions will remain unanswered.

Declaration of interests

Post funded by the Max-Planck Society and the University of Heidelberg.