Lithium inhibition of bone mineralization and osteoid formation.

Baran, Daniel T.; Schwartz, Meyer P.; Bergfeld, Michele A.; Teitelbaum, Steven L.; Slatopolsky, Eduardo; Avioli, Louis V.

doi:10.1172/jci109090

Cited by 29 publications

(17 citation statements)

References 22 publications

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“…The large volume of blood required to measure plasma lithium precludes obtaining serial measurements in mice. There have been conflicting reports on the effect of LiCl on bone metabolism in larger animals such as the rat (42)(43)(44). However, these disparities likely reflect methodologic differences in study design and interpretation.…”

Section: Discussionmentioning

confidence: 99%

“…In the one study that identified deleterious effects, LiCl was injected i.p. into skeletally immature rats, and serum lithium levels were 1.6 mM (43), which is at the high end of the therapeutic range and associated with an increased incidence of side effects in humans (35). Furthermore, the investigators looked only at cortical bone growth rather than trabecular bone growth.…”

Section: Discussionmentioning

confidence: 99%

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Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice

Clément-Lacroix

Morvan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

462

327

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One of the well characterized cell biologic actions of lithium is the inhibition of glycogen synthase kinase-3␤ and the consequent activation of canonical Wnt signaling. Because deficient Wnt signaling has been implicated in disorders of reduced bone mass, we tested whether lithium could improve bone mass in mice. We gavage-fed lithium chloride to 8-week-old mice from three different strains (Lrp5 ؊/؊ , SAMP6, and C57BL͞6) and assessed the effect on bone metabolism after 4 weeks of therapy. Lrp5 ؊/؊ mice lack the Wnt coreceptor low-density lipoprotein receptor-related protein 5 and have markedly reduced bone mass. Lithium, which is predicted to act downstream of this receptor, restored bone metabolism and bone mass to near wild-type levels in these mice. SAMP6 mice have accelerated osteoporosis due to inadequate osteoblast renewal. Lithium significantly improved bone mass in these mice and in wild-type C57BL͞6 mice. We found that lithium activated canonical Wnt signaling in cultured calvarial osteoblasts from Lrp5 ؊/؊ mice ex vivo and that lithium-treated mice had increased expression of Wnt-responsive genes in their bone marrow cells in vivo. These data lead us to conclude that lithium enhances bone formation and improves bone mass in mice and that it may do so via activation of the canonical Wnt pathway. Lithium has been used safely and effectively for over half a century in the treatment of bipolar illness. Prospective studies in patients receiving lithium should determine whether it also improves bone mass in humans.anabolic ͉ osteoporosis ͉ therapy

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice

Clément-Lacroix

Morvan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

462

327

View full text Add to dashboard Cite

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“…Various trace elements have already been ascribed a role in the development of bone lesions, e.g., cadmium (45), lithium (46), strontium (16), and, most important, aluminum (2,4,47). Aluminum, in the past also frequently used as a phosphate binder, has been shown to have a direct toxic effect on bone, inhibiting both mineralization (13,14,48) and osteoblast function (3), thus causing the so-called aluminum-related bone disease, expressed as either osteomalacia or adynamic bone disease.…”

Section: Discussionmentioning

confidence: 99%

Does the Phosphate Binder Lanthanum Carbonate Affect Bone in Rats with Chronic Renal Failure?

Behets¹,

Dams²,

Vercauteren³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Adequate control of phosphate levels remains an important issue in patients with chronic renal failure (CRF). Lanthanum carbonate has been proposed as a new phosphate binder. Previous studies have shown a high phosphate binding capacity (Ͼ97%) and low gastrointestinal absorption of lanthanum, without serious toxic side effects in the presence of a normal renal function (NRF). Because of lanthanum's physicochemical resemblance to calcium, the possible effects of it on bone have to be considered. The aim of this study was to investigate the effects of lanthanum carbonate on bone histology in NRF and CRF rats after oral administration of the compound with doses of 100, 500, or 1000 mg/kg per d for 12 wk. Bone histomorphometry showed that CRF animals that received vehicle developed secondary hyperparathyroidism. Urinalysis of lanthanum-loaded CRF animals showed a dosedependent decrease in urinary phosphorus excretion, which was clearly more pronounced in the CRF groups compared with NRF animals. Phosphatemia, however, remained normal. Lanthanum carbonate administration induced a dose-dependent decrease in bone formation rate and increase in osteoid area in CRF animals. Three of seven animals in the CRF-1000 group and one of eight animals in the NRF-100 group were classified as having a mineralization defect. The number of cuboidal osteoblasts, however, was not affected, indicating that bone changes were not due to a toxic effect of lanthanum on the osteoblast. Furthermore, lanthanum concentrations in the femur remained low and did not correlate with histomorphometric parameters. These findings suggest that the administration of high doses of phosphate binder (1000 mg/kg per d lanthanum carbonate), in combination with decreased 25-(OH) vitamin D 3 in the uremic state, resulted in phosphate depletion and followed by an increased mobilization of phosphorus out of bone and/or reduced incorporation into bone. There was no evidence that lanthanum had a direct toxic effect on osteoblasts.

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“…In previous studies we have shown that although lithium chloride administration to rats did not alter serum levels of calcium or iPTH, its administration was associated with decreased rates of bone mineralization and osteoid formation [2]. In order to determine whether the skeletal effects of lithium treatment were secondary to alterations in Send offprint request to D.T.…”

Section: Methodsmentioning

confidence: 99%

Effect of lithium on parathyroid hormone-induced calcium release from bone rudiments

et al. 1979

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Lithium treatment of humans and animals has been associated with adverse effects on bone and mineral metabolism. In order to determine whether lithium was altering the skeletal response to parathyroid hormone, we incubated bone rudiments for 5 days in the presence or absence of the drugs. Lithium had no effect on either parathyroid hormone-induced cyclic AMP generation or 45Ca release from the bone rudiments. The data are consistent with the hypothesis that the skeletal effects of lithium are not mediated via inhibition of the parathyroid hormone-adenyl cyclase-cyclic AMP system.

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Lithium inhibition of bone mineralization and osteoid formation.

Cited by 29 publications

References 22 publications

Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice

Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice

Does the Phosphate Binder Lanthanum Carbonate Affect Bone in Rats with Chronic Renal Failure?

Effect of lithium on parathyroid hormone-induced calcium release from bone rudiments

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