Osteoporosis Drugs Prevent Bone Loss, Normalize Metabolic Parameters and Negatively Correlate Bone and Fat
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Post-menopausal osteoporosis is associated with bone loss but menopause can also increase body mass and abdominal adiposity, factors that can pose a secondary risk to skeletal health. Drugs such as alendronate (ALN), parathyroid hormone (PTH) and sodium fluoride (NaF) target bone loss but their effects on adiposity, metabolism, and the interrelationship between bone and fat are largely unknown. To this end, we subjected OVX rats to short-term (2 months) and long-term (6 months) treatments of different doses of ALN, PTH and NaF and analyzed body weight, vertebral bone, abdominal fat volume, liver fatty acids, and serum leptin and IGF-I. Six-month old Sprague-Dawley rats were assigned to age-matched controls, untreated OVX, OVX treated with high (H), medium (M), or low (L) doses of hPTH (60, 15, or 0.3 ug/kg/d), or OVX treated with H, M, or L-ALN (100, 10, or 1 ug/kg/2xwk) or OVX treated with H or L-NaF (500ppm or 100ppm in drinking water). Rats were sacrificed at 6, 8, and 12 months of age (n=10/group/age). Body mass and fat accumulation was strongly influenced by age. Age-matched controls gained 12.7% more weight throughout the course of the study than OVX controls and weighed 10% less, while treated animals gained 28.1% less weight than OVX controls and weighed 4.9% less. At 12 months of age, H-ALN treatment had 37.8% less subcutaneous fat than OVX controls. (p<0.01) By 12 months all treated animals had smaller fat pads than OVX controls.(p<0.05) Liver esterfied free fatty acid (NEFA) concentrations were smaller at 8 months in H-PTH and L-ALN rats compared to OVX controls.(p<0.05) At 12 months, all groups except M-ALN had lower liver triglyceride (TG) and NEFA concentrations than OVX controls.(p<0.05) At 8 months, H-, M- and L-ALN as well as H- and M-PTH showed higher vertebral bone apparent density (in vivo uCT) than OVX controls.(p<0.05). Both H- and M-PTH had higher trabecular thickness (ex vivo uCT) while only H-PTH had higher bone volume fraction than OVX controls.(p<0.05) At 12 months and compared to OVX controls, apparent vertebral densities (in vivo uCT), trabecular number and trabecular apparent densities (ex vivo uCT) were significantly higher in H-, M-, and L-ALN, H-, and M-PTH groups as well as H-NaF, while trabecular spacing was decreased.(p<0.05) However, high doses of ALN and PTH suppressed IGF-I levels.(p<0.01) Body mass was positively correlated to bone volume and density for age-matched controls with high dose treatment groups (r2= 0.36, p<0.01), but was not correlated in the OVX controls with low dose treatments. Liver TG content was not correlated to bone volume fraction in OVX controls (r2=0.001, p<0.93), but ALN, PTH and NaF treatment normalized this relationship to that seen in age-matched controls. ALN and PTH treatment reduced the elevation of the total fat to body mass relationship compared to age matched controls, indicating a reduction due to treatment. OVX controls showed no correlation between bone density and liver TG, while AM controls and NaF showed a positive relationship. All ALN treatment groups combined and H and M- PTH treatment groups combined both showed negative correlations between density and liver TG content; the highest responders to treatment had the lowest TG concentrations. These data demonstrate that treatment with moderate to high doses of ALN, PTH and NaF can normalize bone morphology and indices of fat metabolism to those of normal age-matched controls. Treatments slowed the rate of weight gain throughout the course of the study while decreasing fat accumulation. ALN and PTH were able to reverse the association between fat and apparent mineral density; demonstrating a secondary positive effect of treatment on fat metabolism. Drug therapies can reduce the severity of post-menopausal osteoporosis but they also reduce fat accumulation and could lower the incidence of menopause related obesity.