Osteoporosis is a high-incidence degenerative disease of the skeleton characterized by loss of bone mass and strength. Although it is not a life-threatening disease its impact on the quality of life is significant as it frequently results in fractures that may lead to chronic pain and disability Citation[1]. Presently, at least 10 million Americans over the age of 50 years have osteoporosis and an additional 33–34 million have osteopenia, a preosteoporotic condition Citation[2]. Importantly, one in two women and one in five men older than 50 are expected to have an osteoporotic fracture in their remaining lifetime Citation[1]. Due to the increase in life expectancy, osteoporosis incidence should only increase in the future along with its burden to the healthcare system. Hence, developing treatments to prevent or treat osteoporosis has been a major goal of modern bone biology.
Skeleton health is dependent on its constant renewal via a process called ‘remodeling’ in which old or damaged bone is replaced by new bone. This remodeling relies on the activity of osteoclasts, the bone-resorbing cells, and of osteoblasts, the bone-forming cells. In an adult healthy skeleton, this resorbing and formation arms of bone remodeling are tightly regulated to maintain a constant mass. Osteoporosis is the result of an imbalance in favor of bone resorption leading to bone loss and qualitative changes in skeletal architecture.
The current major tool against osteoporosis is antiresorptive therapy, with the most widely used class of drugs being bisphosphonates and selective estrogen receptor modulators. While antiresorptive therapies are effective at stalling bone loss they cannot restore an adequate bone mass when this loss is already too important. This is a concern since the onset of osteoporosis causes no apparent symptoms and therefore its detection usually occurs only once a significant amount of bone is already lost. Hence, to fully restore bone mass one needs to not only to slow down resorption but also to rebuild the lost bone. At this time, the sole bone anabolic therapy available is intermittent treatment with recombinant parathyroid hormone (PTH, teriparatide). Given by daily injections and being more expensive than antiresorptive therapies it is only approved for patients with high risk of fracture or with unsatisfactory response to other therapies. Furthermore, the recommended duration of treatment is relatively short (2 years in the USA and 18 months in Europe). Lastly, co-therapy with teriparatide and antiresorptive drugs does not appear to provide any advantages over monotherapy Citation[3]. This limitation in bone anabolic treatments in the face of a disease of growing incidence is a strong incentive to search for novel pathways that could be targeted to develop drugs specifically stimulating bone formation. Such an opportunity arose 4 years ago when gut-derived serotonin was identified as a negative regulator of bone formation Citation[4].
Inhibiting the synthesis of gut serotonin increases bone formation
Ninety five percent of the serotonin present in our body is synthesized by gut enterochromaffin cells Citation[5] and is released into the general circulation where it is mainly stored in platelets. Approximately 5% of this serotonin, however, remains free in plasma. Gut serotonin biosynthesis is controlled by the rate-limiting enzyme tryptophan hydroxylase 1 encoded by the Tph1 gene Citation[5]. In mice, inactivation of Tph1 in gut cells causes a high bone mass phenotype affecting osteoblast number and bone formation with no changes in osteoclast parameters or bone resorption Citation[4]. Thus, gut-derived serotonin strictly acts on bone formation. Remarkably, the gut-specific inactivation of Tph1 can prevent the loss of bone due to ovariectomy, a classical model of osteoporosis Citation[4]. This beneficial activity could also be observed in mice with only a heterozygous inactivation of Tph1 in gut although the level of blood serotonin in these mutant mice was only reduced by less than half Citation[6]. This latter observation implies that there is no need to completely abrogate gut serotonin production to obtain a significant anabolic effect on bone. Molecular studies demonstrated that gut-derived serotonin directly acts on osteoblasts to limit their proliferation through repression of several cell cycle regulators Citation[4]. Identification of the specific receptor-mediating serotonin signaling in osteoblasts and of a complex interaction of multiple transcription factors downstream of this pathway completed our understanding of serotonin function in osteoblasts Citation[4,7].
The genetic experiments reported above demonstrated that inhibiting serotonin production in the gut could be a means to treat osteoporosis, at least in principle. The clinical potential of this finding, however, became even more evident when this effect could be pharmacologically reproduced with an already available compound. LP533401 is a small-molecule inhibitor of Tph1 that was developed for the treatment of irritable bowel syndrome and had been tested as such in Phase I and II clinical trials Citation[8,9]. This molecule, which inhibits Tph1 bioactivity and therefore limits serotonin biosynthesis Citation[9], was tested for its potential action on bone both in mice and rats Citation[10,11]. In these studies, its daily oral administration rescued the ovariectomy-induced osteoporotic phenotype in both vertebras and long bones, resulting in improved bone quality. As in the Tph1-mutant mice, this positive effect on bone mass was caused by a strict increase in the rate of bone formation, with no effect in bone resorption. Also in agreement with the genetic analysis, a dose of Tph1 inhibitor reducing circulating serotonin only by half was sufficient to revert the bone loss due to ovariectomy. The fact that this treatment preserved a significant level of serotonin in serum and shows poor systemic exposure might explain the absence of side effects observed in these studies Citation[11,12]. Of note, Phase II clinical trials using a much higher dose of this compound did not identify either significant toxicity or side effects Citation[8]. The studies in rodents also highlighted several other features that are important from a therapeutic point of view. First, blocking gut serotonin production could improve bone formation in old ovariectomized mice, a key observation since the highest prevalence of osteoporosis is in the elderly population. Second, the beneficial effect of Tph1 inhibition could be observed upon long-term treatment and persisted after discontinuation Citation[10], two assets considering that bone loss disorders are usually chronic conditions. Third, Tph1 inhibition could be combined with antiresorptive therapy to simultaneously increase bone formation and decrease bone resorption Citation[10].
Inhibiting the synthesis of gut serotonin also positively affects energy metabolism
The bone anabolic action of serotonin inhibition was already attractive from a biomedical point of view, it became even more so when a recent study reported that gut-derived serotonin is also a regulator of glucose metabolism Citation[13]. Indeed, serotonin favors lipolysis and liver gluconeogenesis upon fasting and thereby is involved in the maintenance of glucose levels in blood. It also directly limits glucose uptake by hepatocytes. As a result, reducing gut serotonin production either genetically through Tph1 inactivation in gut cells or pharmacologically using LP533401 significantly improved insulin and glucose intolerance in a diet-induced mouse model of Type 2 diabetes. Because Type 2 diabetes prevalence increases with age, it often coexists with osteoporosis in men and women over 50 years of age. Serotonin inhibition could therefore represent an unforeseen opportunity to treat those two diseases at once.
Where should we go from here?
Since the role of gut-derived serotonin in regulating bone formation has been described in animal models, it is arguable that some of these findings might not transfer, at least partly, in humans. Clinical evidence, however, already exists that show a correlation between circulating levels of serotonin and bone mass accrual. For instance, population-based analyses have linked high levels of blood serotonin with lower bone mineral density and reduced trabecular thickness in adult women and autistic children, respectively Citation[14,15]. Likewise, the severe osteoporosis and repeated fragility fractures reported in a recent case study was ascribed to a pancreatic serotonin-producing tumor Citation[16]. Indirect correlations based on the functional interaction existing between the LRP5 cell surface receptor expressed in gut cells and Tph1 expression also provided several correlative arguments. Loss of function mutations in the LRP5 gene cause a low bone mass syndrome in humans called ‘osteoporosis pseudoglioma’ while gain-of-function mutation in LRP5 cause a high bone mass syndrome. Remarkably, circulating serotonin levels are decreased in high bone mass patients Citation[4,17,18] whereas they are high in patients with osteoporosis pseudoglioma Citation[4,6,19].
Based on these findings it becomes fair to postulate that the inhibition of bone formation by gut-derived serotonin observed in rodents is most likely conserved in humans. Then, testing whether decreasing gut serotonin production also has a bone anabolic effect in humans does appear a sensible thought. Of course, there is no guarantee that such studies will eventually lead to a treatment for osteoporosis but this is, and it has always been, the case for any novel pathway or drug target that has ever been identified by basic science studies. If anything the high and predicted sharp increase in the incidence and medical cost of osteoporosis, combined with the need for novel bone anabolic therapies beg us to explore all opportunities. Tph1 inhibition is a tangible one that should not be ignored.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Holroyd C, Cooper C, Dennison E. Epidemiology of osteoporosis. Best Pract. Res. Clin. Endocrinol. Metab. 22(5), 671–685 (2008).
- Feng X, McDonald JM. Disorders of bone remodeling. Annu. Rev. Pathol. 6, 121–145 (2011).
- Black DM, Greenspan SL, Ensrud KE et al.; PaTH Study Investigators. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N. Engl. J. Med. 349(13), 1207–1215 (2003).
- Yadav VK, Ryu JH, Suda N et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135(5), 825–837 (2008).
- Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132(1), 397–414 (2007).
- Yadav VK, Arantes HP, Barros ER, Lazaretti-Castro M, Ducy P. Genetic analysis of Lrp5 function in osteoblast progenitors. Calcif. Tissue Int. 86(5), 382–388 (2010).
- Kode A, Mosialou I, Silva BC et al. FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin. J. Clin. Invest. 122(10), 3490–3503 (2012).
- Brown PM, Drossman DA, Wood AJ et al. The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with nonconstipating irritable bowel syndrome. Gastroenterology 141(2), 507–516 (2011).
- Liu Q, Yang Q, Sun W et al. Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract. J. Pharmacol. Exp. Ther. 325(1), 47–55 (2008).
- Inose H, Zhou B, Yadav VK, Guo XE, Karsenty G, Ducy P. Efficacy of serotonin inhibition in mouse models of bone loss. J. Bone Miner. Res. 26(9), 2002–2011 (2011).
- Yadav VK, Balaji S, Suresh PS et al. Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat. Med. 16(3), 308–312 (2010).
- Shi ZC, Devasagayaraj A, Gu K et al. Modulation of peripheral serotonin levels by novel tryptophan hydroxylase inhibitors for the potential treatment of functional gastrointestinal disorders. J. Med. Chem. 51(13), 3684–3687 (2008).
- Sumara G, Sumara O, Kim JK, Karsenty G. Gut-derived serotonin is a multifunctional determinant to fasting adaptation. Cell Metab. 16(5), 588–600 (2012).
- Hediger ML, England LJ, Molloy CA, Yu KF, Manning-Courtney P, Mills JL. Reduced bone cortical thickness in boys with autism or autism spectrum disorder. J. Autism Dev. Disord. 38(5), 848–856 (2008).
- Mödder UI, Achenbach SJ, Amin S, Riggs BL, Melton LJ 3rd, Khosla S. Relation of serum serotonin levels to bone density and structural parameters in women. J. Bone Miner. Res. 25(2), 415–422 (2010).
- Vilaca T, Yamamoto R, Carvalho AB, Lazaretti-Castro M. Neuroendocrine tumor associated with severe osteoporosis in a male patient. Endocrine Rev. 32 (2011).
- Frost M, Andersen T, Gossiel F et al. Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5. J. Bone Miner. Res. 26(8), 1721–1728 (2011).
- Frost M, Andersen TE, Yadav V, Brixen K, Karsenty G, Kassem M. Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin. J. Bone Miner. Res. 25(3), 673–675 (2010).
- Saarinen A, Saukkonen T, Kivelä T et al. Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia. Clin. Endocrinol. (Oxf.) 72(4), 481–488 (2010).