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Gut–Bone Interactions and Implications for the Child With Chronic Gastrointestinal Disease

Klein, Gordon L.

Journal of Pediatric Gastroenterology & Nutrition: September 2011 - Volume 53 - Issue 3 - p 250–254
doi: 10.1097/MPG.0b013e3182254828
Invited Review

ABSTRACT: Bone is not simply a framework on which to hang viscera and connective tissue; it is also a dynamic interactive organ system with roles in immunoregulation, adipogenesis, and vascular calcification, among others. Bone is intimately affected by chronic disease, including gastrointestinal disease. The mechanisms for bone loss in conditions such as inflammatory bowel disease, celiac disease, and cystic fibrosis are discussed with regard to the role of the inflammatory response. Furthermore, we raise the issue of effects of inflammation on both intestinal and renal calcium and phosphate transport, although the ways in which these actions affect bone are not explained and require further research. The stress response, a prominent feature following burn injury, is also elucidated and its relation to gastrointestinal disease is examined. We then discuss the importance of knowing the mechanism of bone loss to determine proper prevention and treatment for the bone loss in specific gastrointestinal conditions.

Department of Orthopaedic Surgery and Rehabilitation and, Shriners Burns Hospital, University of Texas Medical Branch, Galveston.

Address correspondence and reprint requests to Gordon L. Klein, MD, MPH, AGAF, Department of Orthopaedic Surgery and Rehabilitation, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-0165 (e-mail:

Received 27 December, 2010

Accepted 11 May, 2011

The authors report no conflicts of interest.

Why should the pediatric gastroenterologist pay attention to bones with all of the severe chronic gastrointestinal, hepatic, and nutritional problems that affect children? The answer in short is that bone is more than just a structural framework on which to hang connective tissue and viscera. Bone is also a hematologic and immunologic organ, because its medulla, or marrow, produces erythrocytes and immunoregulatory cells. The marrow is not independent of its surrounding bony envelope, although all of the interactions between the 2 components are not yet clear; however, the marrow is clearly the source of bone-forming cells, the osteoblasts, and bone-resorbing cells, the osteoclasts. Furthermore, bone proteins such as osteoprotegerin (1), bone morphogenetic protein (2), and RANK ligand (3) are elevated during inflammation and may contribute to the process of intestinal inflammation. Bone may also be an endocrine organ that aids in the regulation of glucose homeostasis (4). In addition, there is an inverse relation between marrow adiposity and its ability to produce bone cells (5). Furthermore, the calcifications within blood vessels are now shown to be the result of intravascular bone formation, complete with an intact Wnt signaling pathway (6) rather than merely calcium deposition overlying damaged endothelial tissue. Moreover, the presence of the calcium sensing receptor in endocardium and aortic endothelium (7) provides further credence to the presence of a bone-forming mechanism with the ability to calcify.

Thus, bone is clearly related to other organ systems and intimately affected by chronic gastrointestinal disease. Work in better defining the relation between gut and bone is under way but still in its early stages. Thus, we do not yet have a comprehensive understanding regarding the nature and implications of this concept. The purpose of the present review, then, is to provide an interim progress report intended to increase the gastroenterologist's appreciation of how gastrointestinal diseases affect bone, to provide additional insights into possible mechanisms at play here by referring to relevant experience gained from the study of burns, and finally to provide an indication of what information is needed in the study of gastrointestinal disease that can define the mechanisms involved in bone loss and to direct specific pharmacotherapy to address these mechanisms.

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To begin with, let us consider some of the diseases that affect both the gastrointestinal tract and bone. Conditions in which some investigation has been conducted include inflammatory bowel disease, particularly Crohn disease, celiac disease, and cystic fibrosis. In these conditions, the reasons for bone loss may be multifactorial and many pathophysiologic mechanisms may remain undiscovered; however, the bone loss is indisputable.

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In Crohn disease, bone loss is often attributed to the therapeutic administration of exogenous glucocorticoids; however, low bone density has been reported at the time of diagnosis (8–10). This finding automatically precludes steroid therapy to be a primary cause, although clearly this treatment may well exacerbate bone loss. In celiac disease (11) and in cystic fibrosis (12), bone loss is usually considered to result from the malabsorption of fats and hence the malabsorption of calcium and vitamin D. The malabsorption would create a classic situation of high-turnover bone loss as a consequence of the secondary hyperparathyroidism that stems from lower serum levels of calcium and vitamin D. The high-turnover state of the bone would not give newly formed bone adequate time to form mature hydroxyapatite crystal, resulting in defective bone calcification, a condition known as osteomalacia. It is also conjectured (12) that pulmonary inflammation results in increased circulating resorptive cytokines and that steroid treatment would also contribute to bone loss in cystic fibrosis and celiac disease. At least in the case of Crohn disease, the most prominent findings to date include reduced bone formation and linear growth (9); it is unclear whether other mechanisms are also operative. Therefore, until the loss of bone or calcium can be adequately explained, appropriate measures to prevent or treat the bone loss cannot be undertaken.

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Although the relation between malnutrition and bone loss is complex, it also must be addressed not by the identification of a specific, correctable pathophysiologic mechanism but by a variety of effects on the body, including poor nutrient intake, delayed onset of puberty, possible malabsorption of calcium or vitamin D, among others (13). Furthermore, malnutrition-associated sarcopenia may lead to reduced skeletal loading, resulting in reduced bone mass.

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To better understand some of the mechanisms of bone loss, it is instructive to bring into the discussion what has been learned from the study of severely burned children during the last 2 decades. Although on the surface there would not appear to be a relation between these burned children and those experiencing chronic gastrointestinal illness, when one probes a bit more deeply into the body's adaptive responses, one finds similarities. The underlying assumption is that mankind did not evolve to survive burn injury inasmuch as this is a relatively rare occurrence. Rather, the response to burn injuries uses whatever adaptive mechanism the body has evolved and the consequences of the utilization of these marginally appropriate mechanisms does have consequences for the body. The 2 adaptive responses we consider here are the stress response and the inflammatory response.

In burns both of these responses occur acutely. The stress response, which consists of endogenous glucocorticoid and catecholamine production has been shown to be massive, with urine free cortisol excretion ranging from 3 to 8 times the upper limit of normal, depending on what is considered the pediatric upper limit of normal (14,15). The endogenous glucocorticoid response is sustained for at least 9 and often 12 months postburn (16). The catecholamine response is more variable and less predictable. Acutely glucocorticoids stimulate the osteoblasts and perhaps the osteocytes as well to produce the ligand of the receptor activator for nuclear transcription factor κB, otherwise known as RANK ligand or simply as RANKL. RANKL stimulates the marrow stem cells that differentiate into the white blood cell line to differentiate instead into osteoclasts or bone-resorbing cells.

Similarly, proinflammatory cytokines, specifically interleukin (IL)-1β and IL-6, stimulate osteoclastogenesis by the same mechanism. Thus, one may hypothesize that there is significant acute bone resorption and initial bone loss; however, after approximately 2 weeks of putative high rate of bone resorption, the osteoblasts disappear from the bone surface (15) and marrow stromal cell differentiation into osteoblasts slows (15). The lack of osteoblasts greatly reduces the RANKL production, which in turn reduces bone resorption (14). Similarly, lack of osteoblasts will reduce type I collagen production for matrix formation and result in low bone formation in both children (14) and adults (17). These effects on the osteoblasts are characteristic of glucocorticoids.

To demonstrate that in the absence of RANKL the cytokines still possess extrainflammatory activity, it has been demonstrated in burned sheep that there is an upregulation of the parathyroid gland calcium sensing receptor, which can lead to hypocalcemia, hypoparathyroidism, and urinary calcium wasting (18). This cytokine-mediated upregulation has been documented by in vitro studies (19,20). Thus, endogenous glucocorticoid production resulting from the stress response and inflammation may act synergistically at first to produce bone resorption and bone loss, and then the glucocorticoid response dominates as the osteoblasts become apoptotic and the bone becomes adynamic, in a low-turnover state. Thus, the bone becomes burned out. Figure 1 illustrates the different mechanisms so far identified to be associated with bone loss.

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Given the scenario in the burn patient, it becomes clear that children with inflammatory bowel disease, celiac disease, and cystic fibrosis to varying degrees also exhibit an inflammatory response. Evidence that patients with Crohn disease experience inflammation-related bone damage comes from Sylvester et al (9,21) and the Leonard group (22). They have shown that the use of infliximab has halted or reversed low bone density. In the case of celiac disease, a recent study (23) demonstrated that children who did not adhere to their gluten-free diet and had positive anti-endomyseal antibodies had a lower lumbar spine bone mineral density than those who did adhere to their strict gluten-free diet and had no anti-endomyseal antibodies. Thus, inflammatory bone loss likely contributes to the pathophysiology of low bone mass in patients with chronic gastrointestinal illnesses.

In the burn patient, we know that the endogenous glucocorticoid production is elevated 3 to 8 times above the upper limit of normal (14,15), as represented by urinary free cortisol excretion. These quantities are associated with the absence of osteoblasts from the bone surface and reduced biomarkers of osteoblast differentiation in vitro when marrow stromal cells are isolated from bone biopsy specimens from burn victims and unburned controls (15). These data suggest that endogenous glucocorticoids can affect bone in a manner similar to exogenously administered steroids. How do these data apply to patients with gastrointestinal disease? It is difficult to know at present, but we do know that an intense inflammatory response by itself can trigger a stress response.

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What Information Do We Need to Determine Whether the Stress Response Occurs in Gastrointestinal Disease?

To determine whether the stress response occurs in inflammatory gastrointestinal disease, it would be necessary to correlate urine free cortisol with disease severity markers, such as the Pediatric Crohn Disease Activity Index or C-reactive protein, and with bone mineral content and density adjusted for body height. The intensity of the inflammatory response may determine whether the stress response is triggered. This relation may be linear or there may be a threshold effect. Therefore, it is possible that a certain degree of inflammation may trigger only resorptive bone loss, and an antiresorptive agent, such as a bisphosphonate, may be the treatment of choice. Once the stress response is triggered and the adynamic bone or low-turnover state sets in, an anabolic agent may be required. We discuss pharmacotherapy below but raise the issue here to illustrate why differentiating between the resorptive and low-turnover responses is important.

To best evaluate the stress or inflammatory effects on bone, one should attempt to obtain a dynamic evaluation by measuring biomarkers of bone formation and resorption. The markers could then be correlated with the dual-energy x-ray absorptiometric determination of areal bone density of the lumbar spine, as a representative of trabecular bone, and the total body less head bone mineral content, as a measure of cortical bone. Both parameters should be adjusted for body height inasmuch as the dual-energy x-ray absorptiometric process tends to overread bone density in larger individuals and underread bone density in smaller individuals. Once volumetric bone density determination becomes widely available, such as with machines that measure peripheral quantitative computed tomography of the distal appendicular skeleton, we will also be able to correlate the biomarkers of bone turnover and the biomarkers of disease severity with volumetric bone density and bone strength.

Commonly used biomarkers of bone formation include osteocalcin, an osteoblast protein the synthesis of which is both vitamin D and vitamin K dependent, which has recently been suggested to aid in the regulation of glucose homeostasis (4) and bone-specific alkaline phosphatase. Biomarkers of bone resorption in use are either serum or 24-hour urine determinations of either the N-telopeptide or the C-telopeptide of type I collagen. N-telopeptide has also been identified in skin, thus making it inappropriate for the measure of bone resorption in children with burns. Similar information is not available with regard to C-telopeptide. These breakdown products of type I collagen are liberated during bone resorption. It is important to note that although many assays for these biomarkers are commercially available, it is important to choose only those assays for which there are normal values for children.

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How Can We Prevent or Treat Potential Bone Loss in Chronic Gastrointestinal Disease?

Once the bone dynamics are understood in relation to disease severity, investigations into the appropriate methods of prevention or treatment must begin. To date, the Food and Drug Administration has not approved any drug to improve bone structure or function in children. Thus, any treatment offered to a child with bone loss stemming from chronic gastrointestinal disease is at best considered off-label use of an approved drug. No pharmacokinetic studies have been undertaken in children using these bone-active agents; however, investigation of these drugs for use in the setting we presently discuss will be necessary to ensure safety and efficacy. The drugs to be considered are antiresorptive agents, particularly the bisphosphonates, and anabolic agents to build up new bone, primarily recombinant human growth hormone (rhGH), and the anabolic steroid oxandrolone. There are newer antiresorptive agents, such as the antibody to RANKL, denosumab, which appear promising in limited use in adults, and anabolic agents such as parathyroid hormone and the anti-sclerostin antibody, which presently cannot be used in children.

Bisphosphonates are the only antiresorptives used off-label in children. There are no clear indications for their use, and they are most commonly used in children to treat idiopathic juvenile osteoporosis or osteogenesis imperfecta. Documentation of safety and efficacy of bisphosphonates in children is available for only 2 conditions, in which the uses of 1 bisphosphonate in particular were widely different.

How do bisphosphonates work? A greatly detailed and greatly readable article on this subject was published by Russell (24). Briefly, the present generation of nitrogen-containing bisphosphonates work by adhering to the bone matrix. They are then taken up by osteoclasts through the process of endocytosis as the osteoclasts resorb the adherent bone matrix. Once inside the osteoclast, the bisphosphonate interferes with cholesterol biosynthesis where it impairs action of the enzyme farnesyl pyrophosphate synthase. As the cell lipid membrane is disrupted, it cannot anchor various signaling proteins to it and thus disrupts osteoclast function, resulting in apoptosis.

In patients with osteogenesis imperfecta, bisphosphonates have been used long-term, that is, for at least 5 years. In burn patients, bisphosphonates have been given only acutely, within 10 days of the burn injury, and not subsequently.

Oddly enough, osteogenesis imperfecta does not feature the abnormality of excessive resorption. Instead, there are at least 7 identified forms of the disease, 5 of which demonstrate mutations in the COL1A1 gene (25). These conditions by and large result in bone pain, reduced bone density, and fractures. The pioneering work of Glorieux's group (26) in Montreal has shown in a series of publications that intravenous administration of pamidronate from 2 to 4 times per year depending on age results in reduced bone pain, reduced fracture rate, and higher bone density. There was no impairment of growth, no atypical femoral fractures, and no osteonecrosis of the jaw.

With regard to burns, the use has been radically different. In an attempt to stop acute resorption assumed to take place immediately after the injury, intravenous pamidronate, 1.5 mg · kg−1 · dose−1, was given within 10 days of the burn injury and again 1 week later. No further doses were administered. This type of use preserved both trabecular and total body (predominantly cortical) bone mass acutely and for up to 2 years postburn (27,28). There were no side effects in this use.

When excessive bone resorption is not the issue but lack of bone formation is, then an anabolic agent is called for. Only 2 such agents have been used in children: one is rhGH (29,30) and the other is the anabolic steroid oxandrolone (31). Both drugs have been used to increase bone in acutely burned pediatric patients. In both of these trials (29,31), it has taken daily administration for 1 year to increase bone mineral content but not bone mineral density. This failure to increase bone mineral density occurs because areal bone density is the quotient of bone mineral content and bone area. Thus, proportional increases in both bone mineral content and bone area while not increasing bone density will lead to a bigger and biomechanically stronger bone. There were no side effects of rhGH including premature epiphyseal closure or hyperglycemia, but there were 2 cases of clitoral hypertrophy (31) with the use of oxandrolone, although this was reversed in both instances with cessation of the drug.

Recombinant human parathyroid hormone has been proven to significantly increase bone density in postmenopausal women when given subcutaneously every day for 1 year (32), but this treatment is prohibited in children by the Food and Drug Administration because administration of this drug in rats has resulted in increased development of osteogenic sarcoma (33). With regard to the newly available anti-sclerostin antibody, only limited use in adults has been reported.

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Influence of the Gut–Renal Axis on the Gut–Bone Axis: What We Know About Inflammation

It is not only a direct effect of intestinal inflammation on bone that we are looking at but also an effect of intestinal inflammation on 2 other major components of bone strength, the calcium and phosphate transport systems.

Although the stress response may be an understudied mechanism of reduced bone formation and may be triggered by the inflammatory response, the latter may also affect a variety of other mechanisms that are only partly understood but which may play a major role in bone loss. Among them is its effect on genes that control the process of bone formation. One of the most critical pathways in the differentiation of marrow stromal cells into osteoblasts is the activation of the lipoprotein-related receptor protein5 and its stimulation of the Wnt glycoprotein to stabilize the nuclear transcription factor β catenin, an important step in osteoblast differentiation. Studies by Heiland et al (34) indicated that Dkk-1, an inhibitor of lipoprotein-related receptor protein5, could trigger inflammation and stimulate the production of sclerostin by the SOST gene. Sclerostin production by osteocytes leads to osteocytic apoptosis.

Moreover, a cytokine produced by inflammation, tumor necrosis factor (TNF)-α, has been shown to downregulate the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene. Inactivating mutations of the PHEX gene result in vitamin D–resistant, X-linked hypophosphatemic rickets. PHEX itself works by inhibiting renal tubular phosphate reabsorption. Studies by Majewski et al (35) have demonstrated that this gene, which encodes a zinc endopeptidase expressed in osteoblasts and contributes to bone mineralization, in 2 models of colitis found that the TNF-mediated downregulation of the gene by poly(ADP-ribose) polymerase 1 binding was immediately upstream of the NF-κB sites, there being an inverse relation between NF-κB signaling and PHEX transcription.

In addition to bone, calcium and phosphate transport also may be affected adversely by inflammation. One aspect of the calcium transport system that may be adversely affected is that of the transient receptor potential (TRP) V5 and V6 subgroups. These proteins are 74% homologous. TRPV5 is expressed predominantly in the distal convoluted tubules of the kidney, where it plays a role in the active reabsoption of calcium. TRPV6 localizes to the duodenal brush border membrane of the enterocyte, where it may mediate transcellular calcium entry (36). In a mouse model of Crohn disease, Huybers et al (37) demonstrated that both TRPV5 and -6 showed significant reduction of mRNA levels. These reduced levels were found in conjunction with reduced serum 1,25-dihydroxyvitamin D and increased markers of bone resorption.

Transepithelial phosphate transport in the gut and the kidney is primarily carried out by the type II group of transporters, which include types IIa, IIb, and IIc (38). Types IIa and IIc are primarily responsible for regulating plasma P concentration in a narrow range, whereas IIb is localized to the intestinal brush border membrane (38) and handles dietary phosphate absorption.

1,25-Dihydroxyvitamin D also contributes to phosphate homeostasis by stimulating intestinal calcium and phosphate absorption. Parathyroid hormone helps to control the phosphatemic effect of 1,25-dihydroxyvitamin D by promoting phosphaturia, which is affected by internalization of type IIa and type IIc transporters and their destruction in intracellular lysosomes (38). Additionally, 1,25-dihydroxyvitamin D transcriptionally activates expression of fibroblast growth factor (FGF) 23 in osteoblasts. FGF23 can in turn reduce serum P levels by inhibiting type IIb transporters through a vitamin D receptor–dependent mechanism. It can also inhibit the renal enzyme 25-hydroxyvitamin D-1-α-hydroxylase, thereby reducing circulating levels of 1,25-dihydroxyvitamin D. Moreover, the protein Klotho, named after the Greek goddess who helps life unfold (39), is a cofactor for FGF23 and helps stabilize the binding of FGF23 to its receptor.

When considering effects of inflammation on phosphate homeostasis, the role of Klotho again comes up. Thus, in colitis in rats, renal expression of Klotho is downregulated (40). Moreover, Klotho is also found in human CD4+ lymphocytes, where it is markedly reduced in the CD4+ cells of patients with rheumatoid arthritis. Thus, although much more information is needed to put together a clearer picture of how chronic intestinal inflammatory disease may affect calcium and phosphate transport, there are already suggestions in the literature that these activities, along with bone, may be adversely affected in the chronic inflammatory state.

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Although the field of pediatric metabolic bone disease is still in its infancy, it is important that we as subspecialists recognize that some of the chronic diseases affecting our patients affect organ systems other than the one in which we are expert, and that it is the responsiblity of all of us to attempt to determine whether our patients experience such effects and seek the earliest and most effective treatment available.

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The author expresses appreciation to Connie Horak of the graphics department of the Scott and White Hospital for the diagram of the skeleton-regulatory factors.

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1. Sylvester FA, Turner D, Draghi A II, et al. Fecal osteoprotegerin may guide the introduction of second-line therapy in hospitalized children with ulcerative colitis. Inflamm Bowel Dis 2010 [Epub ahead of print].
2. Maric I, Poljak L, Zoricic S, et al. Bone morphogenetic protein-7 reduces the severity of colon tissue damage and accelerates the healing of inflammatory bowel disease in rats. J Cell Physiol 2003; 196:258–264.
3. Tilg H, Moschen AR, Kaser A, et al. Gut, inflammation and osteoporosis: basic and clinical concepts. Gut 2008; 57:684–694.
4. Clemens TL, Karsenty G. The osteoblast: an insulin target cell controlling glucose homeostasis. J Bone Miner Res 2011;26:677–80.
5. Chen JR, Lazarenko OP, Wu X, et al. Obesity reduces bone density associated with activation of PPARγ and suppression of Wnt/β catenin in rapidly growing male rats. PLoS One 2010;5:e13704.
6. Towler DA, Demer LL. Vascular calcification. In: Rosen CJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7th ed. Washington, DC: American Society for Bone and Mineral Research; 2008: 436–42.
7. Klein GL, Enkhbaatar P, Traber DL, et al. Cardiovascular distribution of the calcium sensing receptor before and after burns. Burns 2008; 34:370–375.
8. Ghosh S, Cowen S, Hannan WJ, et al. Low bone density in Crohn's disease but not in ulcerative colitis at diagnosis. Gastroenterology 1994; 107:1031–1039.
9. Sylvester FA, Wyzga N, Hyams JS, et al. Natural history of bone metabolism and bone mineral density in children with inflammatory bowel disease. Inflamm Bowel Dis 2007; 13:42–50.
10. Dubner SE, Shults J, Baldassano RN, et al. Longitudinal assessment of bone density and structure in an incident cohort of children with Crohn's disease. Gastroenterology 2009; 136:35–39.
11. Selby PL, Davis M, Adams JE, et al. Bone loss in celiac disease is related to secondary hyperparathyroidism. J Bone Miner Res 1999; 14:652–657.
12. Aris RM, Merkel PM, Bachrach LK, et al. Consensus statement: guide to bone health and disease in cystic fibrosis. J Clin Endocrinol Metab 2005; 90:1888–1896.
13. Mascarenhas MR, Thayu M. Pediatric inflammatory bowel disease and bone health. Nutr Clin Pract 2010; 25:347–352.
14. Klein GL, Herndon DN, Goodman WG, et al. Histomorphometric and biochemical characterization of bone following severe burns in children. Bone 1995; 17:455–460.
15. Klein GL, Bi LX, Sherrard DJ, et al. Evidence supporting a role of glucocorticoids in short-term bone loss in burned children. Osteoporos Int 2004; 15:468–474.
16. Pereira CT, Jeschke MG, Herndon DN. Beta blockade in burns. Novartis Found Symp 2007; 280:238–248.
17. Klein GL, Herndon DN, Rutan TC, et al. Bone disease in burn patients. J Bone Miner Res 1993; 8:337–345.
18. Murphey ED, Chattopadhyay N, Bai M, et al. Up-regulation of the parathyroid calcium-sensing receptor after burn injury in sheep: a potential contributory factor to post-burn hypocalcemia. Crit Care Med 2000; 28:3885–3890.
19. Nielsen PK, Rasmussen AK, Butters R, et al. Inhibition of PTH secretion by interleukin-1 beta in bovine parathyroid glands in vitro is associated with up-regulation of the calcium-sensing receptor mRNA. Biochem Biophys Res Commun 1997; 238:880–885.
20. Toribio RE, Kohn CW, Capen CC, et al. Parathyroid hormone (PTH) secretion, PTH mRNA, and calcium-sensing receptor mRNA expression in equine parathyroid cells, and effects of interleukin (IL)-1,IL-6 and tumor necrosis factor alpha on equine parathyroid cell function. J Mol Endocrinol 2003;31:609–20.
21. Sylvester FA, Davis PM, Wyzga N, et al. Are activated T cells regulators of bone metabolism in children with Crohn's disease? J Pediatr 2006; 148:429–432.
22. Thayu M, Leonard MB, Hyams JS, et al. Improvement in biomarkers of bone formation during infliximab therapy in pediatric Crohn's disease: results of the REACH study. Clin Gastroenterol Hepatol 2008; 6:1378–1384.
23. Blazina S, Bratanii N, Sirca Campa A, et al. Bone mineral density and importance of a strict gluten-free diet in children and adolescents with celiac disease. Bone 2010; 47:598–603.
24. Russell RG. Bisphosphonates: mode of action and pharmacology. Pediatrics 2007; 119 (suppl 2):S150–S162.
25. Ward LM, Rauch F, Whyte MP, et al. Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study. J Clin Endocrinol Metab 2011;96:355–64.
26. Glorieux FH, Bishop NJ, Plotkin H, et al. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998; 339:947–952.
27. Klein GL, Wimalawansa SJ, Kulkarni G, et al. The efficacy of acute administration of pamidronate on the conservation of bone mass following severe burn injury in children. Osteoporos Int 2005; 16:631–635.
28. Przkora R, Herndon DN, Sherrard DJ, et al. Pamidronate preserves bone mass for up to two years following acute administration for pediatric burn injury. Bone 2007; 41:297–302.
29. Hart DW, Herndon DN, Klein G, et al. Attenuation of post-traumatic muscle catabolism and osteopenia by long-term growth hormone therapy. Ann Surg 2001; 233:827–834.
30. Branski LK, Herndon DN, Barrow RE, et al. Randomized controlled trial to determine the efficacy of long-term growth hormone treatment in severely burned children. Ann Surg 2009;250:514–23.
31. Murphy KD, Thomas S, Mlcak RP, et al. Effects of long-term oxandrolone administration in severely burned children. Surgery 2004; 136:219–224.
32. Finkelstein JS, Wyland JJ, Lee H, et al. Effects of teriparatide, alendronate, or both in women with post-menopausal osteoporosis. J Clin Endocrinol Metab 2010; 95:1838–1845.
33. Vahle JL, Sato M, Long GG, et al. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicol Pathol 2002; 30:312–321.
34. Heiland GR, Zwerina K, Baum W, et al. Neutralization of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression. Ann Rheum Dis 2010;69:2152–9.
35. Majewski PM, Thurston RD, Ramalingam R, et al. Cooperative role of NF-{kappa}B and poly (ADP-ribose) polymerase 1 (PARP-1) in the TNF-induced inhibition of PHEX expression in osteoblasts. J Biol Chem 2010; 285:34828–34838.
36. Wu L-J, Sweet T-B, Clapham DE. International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family. Pharmacol Rev 2010; 62:381–404.
37. Huybers S, Apostolaki M, van der Eerden BCJ, et al. Murine TNF ΔARE Crohn's disease model displays diminished expression of intestinal Ca2+ transporters. Inflamm Bowel Dis 2008; 14:803–811.
38. Kiela PR, Ghishan FK. Recent advances in the renal-skeletal-gut axis that controls phosphate homeostasis. Lab Invest 2009; 89:7–14.
39. Drueke TB, Prie D. Klotho spins the thread of life: what does Klotho do to the receptors of fibroblast growth factor-23 (FGF-23)? Nephrol Dial Transplant 2007; 22:1524–1526.
40. Thurston RD, Larmonier CB, Majewski PM, et al. Tumor necrosis factor and interferon-gamma down-regulate Klotho in mice with colitis. Gastroenterology 2010; 138:1384–1394.

anabolic agents; antiresorptives; bone; calcium transport; cystic fibrosis; inflammatory bowel diseases; inflammatory response

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