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Recently, we showed that supplementation with nitric oxide (NO) via donor nitroglycerin (NG) alleviated the ovariectomy and corticosteroid-induced bone loss in rats. In humans, high doses or frequent applications of NG (i.e., for angina) lead to rapid loss of its efficacy in relieving angina. To examine whether there is a similar effect on the loss of efficacy of NG on bone, we examined the frequency-dependent effects of NG on bone mineral density (BMD), bone mass, trabecular bone volumes (BV/TV), and blood pressure in rats. Thirty 7-month-old female Brown Norway rats underwent ovariectomy, and an additional six rats were shamoperated. The ovariectomized rats were treated either with vehicle (ovariectomized control), 17␤-estradiol (E 2 ; positive control), or 0.2 mg NG (via dermal application) once, twice, or three times a day. Before and at the end of the 10-week treatment period, BMD of the lumbar spine was measured by dual-energy X-ray absorptiometric (DXA) scanning and expressed as a percentage change. BMD in ovariectomized rats was significantly lower (؊2.5 ؎ 2.0%) compared with the sham-operated rats (؉6.3 ؎ 5.3%; p < 0.01). Estrogen therapy completely abolished the ovariectomy-induced potential bone loss (؉5.9 ؎ 3.4%). Application of NG once daily also completely prevented (؉6.2 ؎ 2.8%; p < 0.01) the ovariectomy-induced bone loss (i.e., it was as effective as estrogen). However, the beneficial effects of NG on BMD were significantly reduced with increased frequency of application of NG (؉1.9 ؎ 2.1%, twice a day and ؊0.2 ؎ 3.3% three times a day). Estrogen or once daily administration of NG preserved femur weights, BV/TV, and decreased urinary deoxypyridinoline levels as expected. However, a higher level of serum osteocalcin and bone-specific alkaline phosphatase levels were maintained only with once daily administration of NG. There were no adverse effects of these doses of NG on blood pressure, but a tendency to lower blood pressure was noticed with increased frequency of NG. These results confirmed our previous findings that NO donors counteract the bone loss associated with estrogen deficiency. However, these beneficial effects of maintaining BMD are lost with increased frequency of NG application. (J Bone Miner Res 2000;15:1119 -1125) Key words: bone mineral density, osteoporosis, postmenopausal bone loss, osteocalcin, estrogen, nitric oxide synthase.

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The benefits of using thyroxine (T4) plus triiodothyronine (T3) in combination in thyroid hormone replacement are unproven but many individuals continue to be treated with this regime. When T3 is used alone for hypothyroidism, it results in wide fluctuations of thyroid hormone levels. However, only limited data exists on combined T3/T4 therapy. In this study, we have compared 24-hour profiles of thyroid stimulating hormone (TSH), free T4 (fT4) and free T3 (fT3) and cardiovascular parameters in 10 hypothyroid patients who had been on once daily combined T3/T4 therapy for more than 3 months with 10 patients on T4 alone. Twenty patients, who were part of a larger study, investigating the long-term benefits of combined T3/T4 therapy, were recruited into this sub-study. Over 24-hours, 12 samples were taken for thyroid hormones. Their 24-hour pulse and BP is also monitored on a separate occasion. On T4 alone, a modest 16% rise in fT4 with no change in fT3 was seen in the first 4-hours post-dose. In contrast, on combined treatment, fT3 levels showed a marked rise of 42% within the first 4-hours post-dose (T3/T4:T4=6.24: 4.63 mU/L, p<0.001). Mean exposure to fT3 calculated by area under the curve (AUC) was higher (T3/T4:T4=1148:1062, p<0.0001) on T3. Circadian rhythm of TSH was maintained on both treatments. No difference in pulse or blood pressure over the 24-hours was seen between the groups. Our data suggests that despite chronic combined T3/T4 therapy, wide peak-to-trough variation in fT3 levels persists. Although no immediate cardiovascular effects were seen, the long-term consequences for patients on combined therapy are unknown.