Anti-Epileptic Drugs And Bone Loss

Drugs against epilepsy can cause bone loss, particularly in post-menopausal women.  A study in rats demonstrated that this is due to changes in Wnt signaling and this effect was especially pronounced in ovariectomised rats, showing that estrogen loss from menopause can enhance the problem. Abstract:

Secondary osteoporosis is the major concern associated with long term intake of antiepileptic drugs (AEDs). Women are the vulnerable targets owing to post-menopausal bone loss. In the present work, we evaluated the effect of 10 weeks of treatment with AED therapy (carbamazepine, CBZ, 75 mg/kg; sodium valproate, SVP, 300 mg/kg; levetiracetam, LTM, 150 mg/kg) on bone mineral density and microarchitecture at femoral epiphysis, lumbar vertebrae and proximal tibia of normal and ovariectomised Wistar rats. In addition, we measured serum levels of vitamin D, receptor activator of nuclear factor kappa β-ligand (RANKL), procollagen type 1 amino-terminal propeptide (P1NP) and wnt inhibitors (sclerostin and DKK-1) following AED therapy. Micro-computed tomography analysis of bones revealed significant reduction in BMD at femur epiphysis and lumbar vertebrae with all the three AEDs evaluated. At proximal tibia, only CBZ showed a significant decline. The reduction in BMD was more pronounced in ovariectomised rats. AEDs also resulted in alteration of micro-CT parameters. These changes were accompanied by an increased serum RANKL with all AEDs while vitamin D levels were reduced only with CBZ treatment and P1NP levels were reduced with SVP and CBZ. Serum sclerostin levels were elevated following all AEDs in normal and ovariectomised rats except with CBZ in normal rats. However, increase in DKK-1 levels was observed with only LTM. Ovariectomy itself resulted in increased RANKL, sclerostin and DKK-1 and reduced vitamin D and P1NP levels. Significant differences were discernible between normal and ovariectomised rats treated with AEDs in all the parameters. However, while sclerostin increased further upon AEDs treatment, P1NP decreased with SVP and CBZ and serum DKK-1 levels showed a declining trend with all the three AEDs studied. We confirm adverse effects on bone following AEDs in female rats. Further, our results demonstrate for the first time that these effects are more pronounced in ovariectomised rats as compared to normal rats and that this could be related to estrogen deficiency which in turn enhances bone resorption via increased RANKL and reduces bone formation via increased sclerostin and reduced P1NP. Finally, our study demonstrated for the first time that AED treatment displayed changes in the serum levels of wnt inhibitors and hence modulation of wnt inhibitors might be partly involved in their adverse effects on bone.

Aging, Androgens, Wnt, And Muscle

Fewer androgen receptors in muscle with age leads to less Wnt5a expression and that leads to less muscle - one explanation for muscle loss with age?  This study was in rats. Abstract:

We sought to determine whether age-related gastrocnemius muscle mass loss was associated with parallel decrements in androgen receptor (AR) or select Wnt signaling markers. To test this hypothesis, serum free and total testosterone (TEST) as well as gastrocnemius AR and Wnt signaling markers were analyzed in male Fischer 344 rats that were 3/6/12/18 and 24 months (mo) old (n=9 per group). Free and total TEST were greatest in 6 mo rats, and AR protein and Wnt5 protein levels linearly declined with aging. There were associations between Wnt5 protein levels and relative gastrocnemius mass (r=0.395, p=0.007) as well as AR and Wnt5 protein levels (r=0.670, p<0.001). We next tested the hypothesis that Wnt5 affects muscle fiber size by treating C2C12-derived myotubes lower (75 ng/mL) and higher (150 ng/mL) concentrations of recombinant Wnt5a protein. Both treatments increased myotube size (p<0.05) suggesting this ligand may affect muscle fiber size in vivo. We next tested if Wnt5a protein levels were androgen-modulated by examining 10 mo old male Fischer 344 rats (n=10-11 per group) that were orchiectomized and treated with testosterone-enanthate (TEST-E), trenbolone enanthate (TREN), a non-aromatizable synthetic testosterone analogue, or a vehicle (ORX only) for 4 weeks. Interestingly, TEST-E and TREN treatments increased Wnt5a protein in the androgen-sensitive levator ani/bulbocavernosus (LABC) muscle compared ORX only (p<0.05). To summarize, aromatizable and non-aromatizable androgens increase Wnt5a protein expression in skeletal muscle, age-related decrements in muscle AR may contribute Wnt5a protein decrements, and our in vitro data imply this mechanism may contribute to age-related muscle loss.

Rats and Colon Cancer

A study shows that dietary risk factors thought to contribute to colon cancer in humans induce early stage colonic lesions in rats.

Epidemiological studies have demonstrated clear associations between specific dietary and environmental risk factors and incidence of colorectal cancer, but the mechanisms responsible for these associations are not known. An animal model could facilitate such an understanding.

Both genotoxic and nongenotoxic carcinogens induce aberrant crypt foci (ACF) in the colons of F344 rats. F344 rats were provided with diets that contained putative risk factors for CRC: low calcium and low vitamin D, high iron, high fructose, and decreased light (UV) exposure or a control diet for 14 wk. The rats were then assessed with biochemical measures and by topological examination for evidence of colon abnormalities. Circulating ionized calcium was decreased from 2.85 to 1.69 mmol/L, and ACF were increased from 0.7 to 13.6 lesions/colon (both P < 0.001).

Rats exposed to the multiple environmental conditions associated with colon cancer, developed ACF similar to the heterogeneous or ill-defined ACF in the human colon. Heterogeneous ACF are the type most frequently seen in humans, and are also seen in rats shortly after exposure to the non-genotoxic colon carcinogen, dextran sulfate sodium. The rodent model could be used to assess the pathways from diet and environment to colon cancer and to provide guidance for clinical studies.

Consider carefully the results with "high fructose" - do we really need high fructose corn syrup in our diets? Also, the "high iron" is another warning shot about red meat.