Long-term aromatase inhibitor use causes bone loss and increases fracture risk secondary to induced estrogen deficiency. We postulated that alfacalcidol (A; vitamin D₃ analog) could help prevent the Letrozole (L)-induced mineral bone loss. Fifty intact 1-month-old female rats were randomly divided into basal group; age-matched control group (AMC); L group: oral administration of 2 mg/kg per day; A group: oral administration of 0.1 μg/kg per day; and group L+A for a period of 8 weeks. Eight-week administration of L resulted in a significant increase in body weight, bone length, bone area, bone formation, and bone resorption activities when compared with the AMC group. However, the bone mass and bone mineral density (BMD) were significantly lower than the AMC group. Serum levels of testosterone, LH, FSH, and IGF-1 were significantly higher and serum estrone and estradiol were lower along with a decrease in ovary+uterus horn weight, when compared with the AMC groups. None of those parameters were affected by A treatment, except suppression of bone resorption activities and increased trabecular bone mass and femoral BMD, when compared with the AMC group. Results of L+A combined intervention showed that bone length, bone area, and bone formation activities were higher than the AMC group, and the bone resorption activities were lower and BMD was significantly higher than that of the L group. This study demonstrates that the combined intervention of L and A not only enhances bone growth, but also increases bone density, and the effects of L and A are independent and additive.

Clinical and in vitro data suggest a link between the elevation of the melanocortin peptide, ACTH, and longitudinal growth. Overproduction of ACTH in familial glucocorticoid deficiency (FGD) is associated with increased growth and ACTH increases the differentiation of chondrocytes along the endochondral pathway in vitro. Using the leptin-deficient obese (ob/ob) mouse along with lean control littermates (n = 9–10), we investigated the effects of adrenalectomy (ADX)-induced elevated ACTH with and without peripheral administration of the MC3-R-specific agonist, γ₂-melanocyte stimulating hormone (γ₂-MSH), on longitudinal growth. Naso-anal and tibial growth were measured together with growth plate parameters; both total and zonal heights together with the proliferative index. Data were analyzed using two-way ANOVA with post hoc comparisons made using the Bonferroni correction. ADX significantly increased naso-anal length in lean mice and ADX plus γ₂-MSH administration significantly increased naso-anal length above ADX alone in ob/ob mice. γ₂-MSH administration to ADX lean and ob/ob mice significantly increased tibial length. In ob/ob mice, these changes occurred in the context of reduced food intake. Analysis of total and zonal growth plate heights suggest an increase in hypertrophic differentiation and an overall increase in growth plate turnover in ADX lean and ob/ob mice. These in vivo data show that ADX enhances linear growth and the results of γ₂-MSH treatment suggest that the melanocortin system plays a role in linear growth.