Rheumatoid arthritis, bone and drugs: a dangerous interweave

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory condition that leads, per se, to bone loss by three main mechanisms. The first one is represented by bone erosions around the involved joints. Second, there is focal subchondral bone loss owing to increased osteoclast activity. Finally, systemic inflammation causes universal bone loss, mainly manifesting at the axial skeleton (ie, vertebral bodies and hip). On the top of this, physical inactivity, also related to lower muscle mass and sarcopenia, further exacerbates bone loss. As a consequence, osteoporosis can be detected in 30%–50% of patients with RA, also depending on age and sex; prevalence and fracture risk both raise with disease duration and seropositivity. The importance of RA in determining both local and systemic osteoporosis is emphasised by the fact that RAis an input variable, as independent risk factor, in the calculation of future fracture risk by FRAX. It is also well known that patients with RA consume a number of drugs to mainly counteract inflammation and pain. However, some of the drugs used have detrimental effects on skeletal tissue, reducing bone strength and ultimately leading to fractures. About 1% of adults in Britain and USA receive longterm oral glucocorticoids mainly for the treatment of joint problems but also for digestive and cutaneous diseases. 4 The longterm or high doses of glucocorticoids use is associated with reduced skeletal strength; indeed, glucocorticoid induced osteoporosis is the most prevalent cause of secondary osteoporosis. Glucocorticoids exert their deleterious effects on bone by acting on the three main cell skeletal lines (osteoblasts, osteoclasts end osteocytes). Among the most important negative effects are: (1) a preferential differentiation of pluripotent precursor cells to adipocytes rather than osteoblasts; (2) a stimulation of the receptor activator of nuclear factorkB (RANK)RANK ligand (RANKL) production which at least initially increase bone resorption and (3) an increased apoptosis of osteocytes with changes in the physical and fluid characteristics of the surrounding territory. These negative effects at the cellular levels contribute to increase the risk of fracture, together with the effects on other organs such as muscle (steroid myopathy) and eye (increased intraarticular pressure and formation of posterior subcapsular cataracts). Proton pump inhibitors (PPI) are drugs widely prescribed in the world. When Food and Drug Administration approved its use as an ‘overthecounter’ drug, there has been a skyrocketing increase in their consumption. Data in Europe mirrored this trend. However, PPIs are associated with a number of side effects among which an increased risk of fracture. Indeed, a number of metaanalyses showed a significantly increased risk of hip and vertebral fractures, with some of them also suggesting a dose–dependent relationship. 8 However, while the biological mechanisms leading to fractures in patients taking glucocorticoids are well ascertained, the same is not true for PPI. Hypothetical mechanisms include a reduced intestinal calcium absorption related to the hypochloridria induced by the negative effects on H/ K ATPase activity. The absorption of other micronutrients important for skeletal health are also adversely affected by longterm PPI use; in particular, PPIs use may be associated with hypomagnesaemia and a doseresponse between the PPIs use and development of hypomagnesaemia has been reported. Other putative mechanisms include an excessive histamine production driven by hypergastrinaemia activated enterochromaffinlike cells (possibly leading to enhanced osteoclastogenesis and bone resorption) together with vitamin B12 deficiency. The last one has been associated with an increased risk of falls and with an increased risk of fractures. 11 In this context, Abtahi et al add important information with implications in clinical practice that should change our behaviour. In summary, they showed that patients with RA taking both GC and PPI have a 1.6fold increased risk of osteoporotic fractures (hip, clinical vertebral, pelvis and ribs) compared with nonusers but also with single users or oral GC or PPI. Merits of this investigation include the large database used together with a long observation period (ie, more than 9 years). However, there are also important weaknesses in addition to those listed by the authors. The most important is represented by the lack of full control for bone active drugs taken by the patients, also including calcium and vitamin D. They claim that these drugs ‘were not considered in the main analysis because of the accompaniment of their prescription with those of oral glucocorticoids and we expect them to lie in the causal pathway of the intended associations of mediators’. However, they do not show any evidence of this assumption nor the use of these drugs in the past 6 months is a guarantee for continuous use during the whole observation period. In addition, and most importantly, their data are not from a randomised controlled study; therefore, confounding cannot be excluded. For example, the populations considered might differ in terms of other factors that predispose or prevent fractures, such as the frequency and type of contact with care health system, physician prescribing attitudes and so on. Bearing in mind these limitations, the most important message coming from this paper is a call for a watchful behaviour by doctors taking care of patients with RA on concurrent GC and PPI treatment. Interestingly, this dangerous liaison has been highlighted in an almost contemporary paper by Miyano et al in patients with antineutrophil cytoplasmic antibody (ANCA)associated vasculitis. Abtahi and coworkers conclude that fracture risk assessment could be considered when a patient with RA is coprescribed oral glucocorticoids and PPIs. This approach that we would say ‘must’ be considered, does not preclude an integration with another approach represented by reducing or deprescribing drugs when they are not needed or when their use is not fully supported by the evidence. This is particularly true, considering the significant number of drugs prescribed to patients with RA that have been associated with an increased risk of fractures. As far as glucocorticoids, the first step should be an attempt to minimise the use of oral glucocorticoids in terms of both dosage and duration. Then, there is clear evidence that the combination of glucocorticoids with nonsteroidal antiinflammatory drugs increase the risk of peptic ulcer disease, thus justifying the concomitant use of PPI. However, there is conflicting evidence Department of Clinical, Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Roma, Italy