Bone loss and wrist fractures after withdrawal of hormone therapy: The 15-year follow-up of the OSTPRE cohort.

CONTEXT: Long-term bone mineral density (BMD) or fracture incidence changes after withdrawal of postmenopausal hormone therapy (HT) are not well known. OBJECTIVE: To study long-term postmenopausal bone loss and incidence of wrist fracture in respect to duration and withdrawal of self-reported HT. DESIGN/SETTING: A 15-year follow-up of the population-based prospective OSTPRE cohort in Kuopio, Finland. PARTICIPANTS: Women (mean baseline age 53.4 years, range 48.1-59.6) were divided into four groups based on duration of HT: (1) never users (non-HT); (2) those who had used HT only throughout the 1st 5-year period (HT5); (3) throughout the first 10-years (HT10); (4) those who used HT throughout the entire 15-year follow-up (HT15). OUTCOME MEASURES: Femoral (n=857) and spinal (n=599) BMD measurements with dual X-ray absorptiometry (DXA) were carried out at 5-year intervals in 1989-2004. Wrist fracture incidence in 1989-2004 was studied in a population of 5119 women. RESULTS: The adjusted spinal BMD (L2-L4) changes by HT use during the entire 15-year follow-up were -4.8% for non-HT (p<0.0001), -4.2% for HT5 (p=0.003), +0.02% for HT10 (p>0.05) and +3.2% for HT15 (p<0.0001) groups. The respective femoral bone losses were -8.6% for non-HT (p<0.0001), -7.9% for HT5 (p<0.0001), -2.5% for HT10 (p=0.010) and -0.2% for HT15 (p>0.05) groups. Comparing to non-HT group the risk of wrist fracture was reduced by 33% (p=0.045) in HT10 group and by 63% (p<0.0001) in HT15 group during the 15-year follow-up. CONCLUSION: Long-term HT-use protects from bone loss. Thus, it reduces the incidence of osteopenia, osteoporosis and wrist fractures. Still, HT-use of less than 5 years did not have long-term bone protective effects, but a larger sample size is needed to confirm this result.

HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial.

OBJECTIVES: We investigated the incidence of new non-vertebral fractures during HRT or low-dose vitamin (Vit) D3 supplementation in a 5-year prospective trial. METHODS: A total of 464 early postmenopausal women, (a subgroup of the Kuopio Osteoporosis Study, n = 13100) were randomized to four groups: (1) HRT, a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate; (2) Vit D (300 IU/day and 100 IU/day during the fifth year); (3) HRT + Vit D; and (4) placebo. Lumbar (L2-4) and femoral neck bone mineral densities (BMD) were determined by dual X-ray absorptiometry (DXA) at baseline, after 2.5 and 5 years of treatment. All new symptomatic non-vertebral, radiographically defined fractures were recorded. RESULTS: Altogether, 368 women (79%) completed the 5 year treatment. In all, 32 women had 39 non-vertebral fractures during a mean of 4.3 year follow-up (HRT 4, Vit D 10, HRT + Vit D 8 and placebo 17). The reduction in the incidence of new non-verterbral fractures was significant in women with HRT alone (P = 0.032) when adjusted by baseline BMD and previous fractures; observed also with the intention-to-treat principle (P = 0.048). When the HRT groups were pooled, HRT showed a significantly lower incidence of new non-vertebral fractures (P = 0.042) than women receiving placebo and also after adjusting as above (P = 0.016); both in valid-case and in the intention-to-treat analysis. In the Vit D group, the fracture incidence was non-significantly decreased (P = 0.229) in comparison with the placebo group. The estimated risk of new non-vertebral fractures among women treated with HRT alone was 0.29 (95% CI, 0.10-0.90) and with Vit D 0.47 (95% CI, 0.20-1.14) and with HRT + Vit D 0.44 (95% CI, 0.17-1.15), in comparison with the placebo group (adjusted by femoral BMD and previous fractures). CONCLUSIONS: This study is the first prospective trial confirming the beneficial effect of HRT on prevention of peripheral fractures in non-osteoporotic postmenopausal women. The effect of low-dose Vit D remains to be proved.

Leucine7 to proline7 polymorphism in prepro-NPY gene and femoral neck bone mineral density in postmenopausal women.

Neuropeptide Y (NPY) is a versatile neurotransmitter that has recently been shown to regulate bone metabolism in animal and in vitro studies. We studied the influence of leucine7-to-proline7 (Leu7/Pro7) polymorphism of the NPY signal peptide gene on bone mineral density (BMD) before and after a 5-year hormone replacement therapy (HRT) in 316 early postmenopausal women participating in a randomized controlled trial nested in the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study. The participants were randomized into two treatment groups: the HRT group (n = 146) received a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate and calcium lactate, 500 mg/day (equal to 93 mg Ca2+) alone or in combination with vitamin D3, 100-300 IU/day. The non-HRT group (n = 170) received calcium lactate, 500 mg alone or in combination with vitamin D3, 100-300 IU/day. BMDs of the lumbar spine (L2-4) and proximal femur were measured by using dual X-ray absorptiometry (DXA). The frequency of Leu7/Pro7 polymorphism was 15.2%. At baseline, there were no significant differences in the lumbar or femoral neck BMD between the subjects who had Leu7Pro7 polymorphism and the normal subjects. After 5 years, the BMD of the femoral neck remained unaltered and that of the lumbar spine increased by 1.7% in the HRT group, whereas both BMDs were decreased by 4-5% in the non-HRT group. After 5 years, the femoral neck BMD was significantly lower in those with the wild-type NPY polymorphism than in those with Leu7/Pro7 polymorphism (P = 0.040) in the non-HRT group. In the HRT group, the changes in BMD were quite modest and not significantly modified by Leu7/Pro7 genotype. We conclude that the Leu7/Pro7 polymorphism in NPY signal gene may favorably affect femoral neck BMD in postmenopausal women.