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Introduction: Peripheral neuropathy occurs in two thirds of patients with diabetes mellitus (DM). It can lead to severe pathological changes in the feet, and it increases the risk of fracture more than any other diabetic complication. The objective of this review is to analyze available literature on the effect of peripheral neuropathy on BMD of the foot, spine, or hip. We hypothesize that the presence of diabetic neuropathy leads to lower BMD in adults with diabetes., Methods: Original studies investigating the effects of diabetic neuropathy on bone density were searched for inclusion in this systematic review. Studies were eligible if they met the following criteria: 1) participants included adults with either Type 1 DM or Type 2 DM; 2) Method used for the diagnosis of neuropathy described in the manuscript 3) DXA scan, ultrasound, or CT scan was used to measure proximal femur, spine, or foot bone mineral density were reported, and 4) bone parameters were analyzed based on the presence and absence of neuropathy., Results: Among the 5 studies that met eligibility criteria, 4 did not find a significant effect of neuropathy on BMD. One study showed a significant negative impact of neuropathy on calcaneal BMD in patients with type 1 diabetes. The meta-analysis did not show a significant effect of peripheral neuropathy on BMDs of proximal femur, spine, and calcaneus in diabetic adults., Conclusion: Our study shows no evidence that peripheral neuropathy affects bone density or bone turnover in DM. However, this conclusion should be taken with caution since only a very limited number of studies were available for inclusion in the analysis and included both type 1 and type 2 DM patients. Improved measures of peripheral neuropathy and more advanced imaging technologies are needed to better assess the effect of diabetes on bone health., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The gap junction protein, connexin43 (Cx43) controls both bone formation and osteoclastogenesis via osteoblasts and/or osteocytes. Cx43 has also been proposed to mediate an anti-apoptotic effect of bisphosphonates, potent inhibitors of bone resorption. We studied whether bisphosphonates are effective in protecting mice with a conditional Cx43 gene deletion in osteoblasts and osteocytes (cKO) from the consequences of ovariectomy on bone mass and strength. Ovariectomy resulted in rapid loss of trabecular bone followed by a slight recovery in wild type (WT) mice, and a similar degree of trabecular bone loss, albeit slightly delayed, occurred in cKO mice. Treatment with either risedronate (20 μg/kg) or alendronate (40 μg/kg) prevented ovariectomy-induced bone loss in both genotypes. In basal conditions, bones of cKO mice have larger marrow area, higher endocortical osteoclast number, and lower cortical thickness and strength relative to WT. Ovariectomy increased endocortical osteoclast number in WT but not in cKO mice. Both bisphosphonates prevented these increases in WT mice, and normalized endocortical osteoclast number, cortical thickness and bone strength in cKO mice. Thus, lack of osteoblast/osteocyte Cx43 does not alter bisphosphonate action on bone mass and strength in estrogen deficiency. These results support the notion that one of the main functions of Cx43 in cortical bone is to restrain osteoblast and/or osteocytes from inducing osteoclastogenesis at the endocortical surface., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We have previously demonstrated that estrogen metabolism is one of the determinants of bone density after menopause. Increased hydroxylation to relatively nonestrogenic metabolites 2-hydroxyestrone (2OHE1) and 2-methoxyestrone (2MeOE1) was associated with low bone mineral density (BMD), while increased hydroxylation to the potent 16alpha-hydroxyestrone (16alphaOHE1) and weakly estrogenic estriol (E3) was associated with higher BMD. In this study, we tested the hypothesis that response to estrogen-hormone replacement therapy (ERT/HRT) is also related to individual differences in estrogen metabolism. Urinary estrogen metabolites were measured in 310 postmenopausal women using ESTRAMET enzyme immunoassay kit. Of these, 163 were on HRT with conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA, Premarin and Provera) or ERT with conjugated equine estrogen alone (Premarin), and 147 women not on ERT/HRT acted as comparison. Annual rates of BMD changes were calculated on a subset of 81 women on ERT/HRT who had more than one previous BMD measured by dual-energy X-ray absorptiometry (DEXA). Controlling for age, years since menopause (YSM), body mass index (BMI), waist to hip ratio, and smoking, we found that urinary estrogen metabolite levels were significantly higher in ERT/HRT-treated women compared to those not on ERT/HRT. Furthermore, women in the higher 2 tertiles of 2OHE1 and 2OHE1/16áOHE1 ratio had positive increments in BMD compared to those in the lowest tertile who lost bone while on ERT/HRT. Thus, women with estrogen metabolism favoring the 2-hydroxylation pathway respond favorably to ERT/HRT.