Effects of alendronate combined with hormone replacement therapy on osteoporotic postmenopausal Chinese women

To evaluate the effect of alendronate combined with hormone replacement therapy (HRT) on postmenopausal osteoporotic Chinese women living in Taiwan, we treated 151 women (age range, 47-70 years; mean, 61 years) with conjugated equine estrogen (0.625 mg), medroxyprogesterone 5 mg, and elemental calcium 500 mg daily with either alendronate 10 mg (n = 79) or placebo (n = 72), and measured their bone mineral density (BMD) at the lumbar spine and hip every 6 months for 3 years. Urine N-telopeptide of type I collagen corrected by concentration of urine creatinine (NTx/Cr) and serum osteocalcin (OC) concentration was also measured at weeks 2, 4, and every 3 months from month 3 for 2 years. Significantly higher percentage increases in BMD at the lumbar spine (P < .0001, 2-way analysis of variance) throughout the 36-month treatment period were found in the alendronate plus HRT group than in the HRT-only group. However, there was no difference in BMD at the femoral neck and trochanter between these 2 groups. Treatment with alendronate plus HRT resulted in a 10.1% increase at the L-spine BMD and a 7.7% increase at the trochanter BMD at the end of the 3-year study period (P < .01, compared with baseline at both sites). A significant decline in urine NTx/Cr was observed at week 4 in the alendronate plus HRT group, whereas in the HRT-only group, a significant decline in urine NTx/Cr occurred at month 9. By the end of 24 months, urine NTx/Cr decreased by 49.7% in the alendronate plus HRT group (P = .001 compared with a 20.4% increase in the HRT group). A significant decline in serum OC level occurred at month 3 in the alendronate plus HRT group, whereas a similar decline was observed at month 6 in the HRT-only group. By the end of 24 months, serum OC decreased by 52.2% in the alendronate plus HRT group (P < .001 compared with a 1.5% increase in the HRT-only group). Subjects treated with alendronate plus HRT had a significantly greater percentage decrease in urine NTx/Cr (P = .0001) and serum OC (P = .0007) than subjects treated with HRT only throughout the 24-month treatment period by 2-way analysis of variance comparison. There was no difference in upper gastrointestinal or drug-related side effects between groups. In conclusion, our data suggest that the use of alendronate combined with HRT for 3 years was well tolerated and it significantly increased BMD at the L-spine and hip in postmenopausal Chinese women with osteoporosis. This regimen is safe and can be used in subjects who have no satisfactory response to a single agent or who have very low BMD with multiple risks. However, this study does not indicate whether HRT plus alendronate has any greater effect on BMD than alendronate alone.     

Bone responsiveness to parathyroid hormone in normal and osteoporotic postmenopausal women

Increased bone loss in estrogen-deficient normal and osteoporotic postmenopausal women may be due mainly to increased sensitivity of bone-resorbing cells to circulating PTH, but this is supported only by indirect data. Therefore, we tested the responsiveness of bone to PTH directly by using a 3-day iv infusion of bovine PTH-(1-34) at 400 U/day in 9 normal premenopausal women, 10 normal postmenopausal women, and 12 osteoporotic postmenopausal women. Serum calcium and urinary hydroxyproline concentrations increased (P less than 0.001) over baseline values during infusion, but the mean increases in both variables did not differ among groups. The data do not support the hypothesis that estrogen deficiency increases the sensitivity of bone to PTH or that the sensitivity in osteoporotic women is greater than that in normal postmenopausal women. Within the constraints imposed by the method of testing, we conclude that the additional bone resorption induced by menopause and by osteoporosis may be due to mechanisms that are not due to enhanced responsiveness of bone to PTH.     

甲状旁腺素联合骨髓间充质干细胞对骨质疏松大鼠股骨颈骨密度相关指标的影响

目的探索骨髓间充质干细胞(BMSCs)联合甲状旁腺激素(PTH)与二者单独使用对骨质疏松性大鼠骨密度相关指标的影响。方法将50只SD雌性大鼠分为A、B、C、D、E组,每组10只,B、C、D、E组切除双侧卵巢,A组大鼠仅切除卵巢周围同等大小的脂肪组织。术后12周各组抽取3只大鼠,检测大鼠的雌激素水平及骨密度相关指标骨小梁数量(Tb.N)、骨小梁厚度(Tb.Th)、骨小梁分离度(Tb.Sp)和骨体积分数(BV/TV)。脱颈法处死SD健康雄性大鼠取骨髓进行BMSCs细胞培养,流式细胞技术单标法检测BMSCs是否培养成功。术后12周,各组剩余7只大鼠。其中A和B组不做后期干预处理;C组按60μg/kg剂量背部皮下注射Rat PTH 1-34,隔日1次,连续12周;D组显露双侧股骨颈,注入浓度为5×108/ml的BMSCs;E组在D组的基础上在皮下注射PTH,注射浓度、频率与C组一致。所有大鼠均在干预12周后处死,Micro-CT测量5组大鼠股骨颈Tb.N、Tb.Th、Tb.Sp和BV/TV,观察成骨情况。使用SPSS 20.0软件进行统计分析。组间比较采用单因素方差分析,有统计学意义再进行LSD两两比较。结果术后12周,与A组比较,B、C、D及E组大鼠雌激素水平、Tb.N、Tb.Th及BV/TV显著下降,Tb.Sp明显升高,差异有统计学意义(P0.05),但B、C、D及E组各组间上述指标差异不明显(P0.05),可证明B、C、D及E组大鼠为骨质疏松模型。流式细胞技术单标法显示,P3代BMSCs表达CD29(99.86%)和CD90(99.73%),几乎不表达CD34(6.48%)和CD45(0.94%),证明BMSCs培养成功。干预12周后,Micro-CT数据显示,单独使用PTH或BMSCs及联合使用均可改善骨微观结构,但均未达到A组水平。与B组比较,C、D、E组的Tb.N、Tb.Th及BV/TV显著增加,Tb.Sp显著下降,差异有统计学意义(P0.05);与C或D组比较,E组Tb.N、Tb.Th及BV/TV显著增加,Tb.Sp显著下降,差异有统计学意义(P0.05)。结论 BMSCs联合PTH治疗局部骨质疏松的效果优于单独使用治疗的效果。     

Enhancement of fracture healing with parathyroid hormone

Since the approval of parathyroid hormone (PTH) as an anabolic treatment for osteoporosis, there has been an increasing interest in other potential clinical uses for this compound in musculoskeletal conditions. Fracture healing is one area of particular interest. It is now widely recognized that daily PTH administration is an effective therapy for increasing bone mineral density and preventing fractures in both male and female osteoporosis patients. More recently, a growing body of evidence supports the conclusion that PTH will also be an effective anabolic therapy for the enhancement of bone repair following fracture. Several animal studies have demonstrated that PTH therapy consisting of daily subcutaneous injections during repair leads to increased callus volumes and a more rapid return of bone strength. Additionally PTH, these reports demonstrated that PTH treatment enhanced repair in older animals, models of osteoporosis, and healthy sexually mature animals. These results underscore the potential of PTH as an anabolic therapy for enhancing the rate of bone repair and regain of mechanical strength in a broad spectrum of fracture patients.     

Histological studies of bone from normocalcemic post-menopausal osteoporotic patients with increased circulating parathyroid hormone.

Quantitative histological evaluations were made of nondecalcified iliac crest needle biopsies were obtained from 16 untreated, normocalcemic, normophosphatemic postmenopausal osteopenic females. Six of the patients had elevated circulating immunoreactive parathyroid hormone. Morphometric parameters, which were significantly increased in the hyperparathyroid group compared with the euparathyroid patients were the cortical osteoclast count and the percentage of trabecular surface covered by active or inactive osteoid. In addition, in all patients, the cortical osteoclast count, and the per cent of trabecular surface covered by osteoid and inactive osteoid were directly related to levels of immunoreactive parathyroid hormone. These data suggest that progressive osteopenia in some patients with crush fracture, or postmenopausal or senile osteoporosis, may be conditioned by an osteoclastosis, elevations in circulating parathyroid hormone, and a relative increase in poorly mineralized osteoid tissue. As such they emphasize the heterogeneity of a so-called "osteoporotic population" and stress the need for specific histological morphometric evaluation of bone before initiating long-term therapeutic modalities.     

Influence of body composition on bone mass in postmenopausal osteoporotic women

We aimed at evaluating the relationship of lean and fat mass to bone mass in osteoporotic postmenopausal women. We invited 65 women who were being treated at the São Paulo Hospital osteoporosis outpatients’ clinic to participate. Body composition and bone mineral density (BMD) measurements were performed using Dual-energy X-ray absorptiometry methodology (DXA). The mean age and weight were 69.7 ± 6.4 years and 56.3 ± 7.6 kg, respectively. Accordingly to the body mass index (BMI), 52.8% were of normal weight and 47.1% of the patients were overweight. Overweight women had significantly higher bone mass. Similarly, skeletal muscle index (SMI) showed a positive effect on BMD measurements and women with sarcopenia had significantly lower BMD measurements in total femur and femoral neck. In multiple regression analysis only lean mass and age, after adjustments to fat mass and BMI, were able to predict total body bone mineral content (BMC) (R² = 28%). Also lean mass adjusted to age and BMI were able to predict femoral neck BMD (R² = 14%). On the other hand, none of the components of the body composition (lean mass or fat mass) contributed significantly to explaining total femur BMD and neither body composition measurements were associated with spine BMD. These findings suggest that lean mass has a relevant role in BMC and BMD measurements. In addition, lower BMI and lean mass loss (sarcopenia) is associated to lower BMC and BMD of femoral neck and total femur and possible higher risk of osteoporotic fracture.     

Hydroxyproline peptides and bone mass in postmenopausal and osteoporotic women.

Total and nondialyzable hydroxyproline excretion was measured in 59 postmenopausal women and 68 women with spinal osteoporosis. Hydroxyproline excretion was similar in both groups of women and the hypothesis that hydroxyproline excretion is normally distributed could not be rejected for either group. No relationship was found between hydroxyproline excretion (total and percentage of nondialyzable) and body weight, height, body surface area, or total body calcium or bone mineral content of the radius, or these latter values normalized for age, sex, and body size. There was no difference in hydroxyproline excretion in osteoporotic women who took supplemental calcium as compared to those that did not. These data fail to provide any evidence that bone turnover in osteoporotic women differs from that in younger postmenopausal women, or that osteoporosis arises from a subpopulation of women with rapid bone loss.     

Effects of alendronate and hormone replacement therapy, alone and in combination, on bone mass and markers of bone turnover in elderly women with osteoporosis

The aim of the study was to compare alendronate, hormone replacement therapy (HRT), and their combination in treatment of osteoporosis in elderly postmenopausal women. Ninety patients, aged 65-80 yr (mean 71), with a T-score of bone mineral density (BMD) of 2.5 or less at either the lumbar spine or the femoral neck were randomized to receive daily 10 mg alendronate (n = 30), 2 mg estradiol plus 1 mg norethisterone acetate (n = 30) (HRT), or their combination (n = 30) for 2 yr. BMD of the lumbar spine and the upper femur was measured at baseline and after 1 and 2 yr of treatment. Urinary excretion of type I collagen aminoterminal telopeptide as related to creatinine and serum type I procollagen aminoterminal propeptide was assayed at baseline and at 6-month intervals thereafter. Increases of 9.1-11.2% in lumbar spine BMD at 2 yr were similar in the study groups. Only HRT increased femoral neck BMD statistically significantly (P < 0.0001 for a change from baseline) at both 1 (+4.9%; P =NS vs. the other groups) and 2 yr (+5.8%; P < 0.05 vs. the other groups). Total hip BMD increased similarly in all study groups. Percentage reductions in urinary type I collagen aminoterminal telopeptide in the HRT group (60.2-62.7%) were significantly smaller than those in the combination group (78.1-80.4%) (P < 0.0001-0.0069) and the alendronate-only group (72.4-76.1%) (P = 0.047 at 24 months). Serum type I procollagen aminoterminal propeptide decreased less in the HRT group (53.6-59.8%) than in the other groups [73.0-75.0% in the alendronate group (P < 0.001 at 12 months); 67.0-71.5% in the combination group (P < 0.0001 at 12 months, P = 0.013 at 24 months)]. We conclude that in elderly postmenopausal women with osteoporosis, the combination of HRT and alendronate did not offer an extra gain of bone mass over either treatment alone. In terms of BMD changes, the single treatments were equally effective, but the reductions in bone markers were less with HRT than with alendronate.     

Regulation of bone mineralization by parathyroid hormone

In randomized clinical trials, parathyroid hormone (PTH) showed potent anabolic effects on the lumbar spine and decreased the risk of incident vertebral fractures dramatically. Although the anabolic effect of PTH on cortical bone in the femoral neck is still unclear, it should be demonstrated in further clinical studies. Concurrent or sequential therapies of PTH and anti-resorptive agents will be one of the major issues of treatment for osteoporosis in the future.     

Enhancement of parathyroid hormone-stimulated bone resorption by poly-L-lysine.

Poly-L-lysine (PL II; mol wt, 1000-4000) was added to fetal rat bones cultured in a chemically defined medium (BGJ) containing bovine serum albumin in the presence and absence of parathyroid hormone (PTH). Bone resorption was measured by the release of previously incorporated 45Ca. The addition of PL II at concentrations of 3-100 microgram/ml enhanced the stimulation of bone resorption by submaximal doses of PTH but had little effect on 45Ca release from control unstimulated cultures. Higher concentrations of PL II produced inhibition of 45Ca release. Dialysis of PL II did not alter enhancement or inhibition by PL II. PL II did not increase sensitivity to PTH in serum-supplemented cultures. Higher molecular weight PL II preparations were less effective. PL II did not enhance the resorptive response to 1,25-dihydroxyvitamin D, prostaglandin E2, osteoclast-activating factor, or bacterial endotoxin. The mechanism of the selective ability of PL II to enhance the response to low concentrations of PTH is unknown but may be due to the ability of this basic polypeptide to interfere with binding of PTH to sites other than the hormone receptor or to block degradation of PTH by bone.     

Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women

GH increases bone turnover and stimulates osteoblast activity. We hypothesized that administration of MK-677, an orally active GH secretagogue, together with alendronate, a potent inhibitor of bone resorption, would maintain a higher bone formation rate relative to that seen with alendronate alone, thereby generating greater enhancement of bone mineral density (BMD) in women with postmenopausal osteoporosis. We determined the individual and combined effects of MK-677 and alendronate administration on insulin-like growth factor I levels and biochemical markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) and resorption [urinary N-telopeptide cross-links (NTx)] for 12 months and BMD for 18 months. In a multicenter, randomized, double blind, placebo-controlled, 18-month study, 292 women (64-85 yr old) with low femoral neck BMD were randomly assigned in a 3:3:1:1 ratio to 1 of 4 daily treatment groups for 12 months: MK-677 (25 mg) plus alendronate (10 mg); alendronate (10 mg); MK-677 (25 mg); or a double dummy placebo. Patients who received MK-677 alone or placebo through month 12 received MK-677 (25 mg) plus alendronate (10 mg) from months 12-18. All other patients remained on their assigned therapy. All patients received 500 mg/day calcium. The primary results, except for BMD, are provided for month 12. MK-677, with or without alendronate, increased insulin-like growth factor I levels from baseline (39% and 45%; P < 0.05 vs. placebo). MK-677 increased osteocalcin and urinary NTx by 22% and 41%, on the average, respectively (P < 0.05 vs. placebo). MK-677 and alendronate mitigated the reduction in bone formation compared with alendronate alone based on mean relative changes in serum osteocalcin (-40% vs. -54%; P < 0.05, combination vs. alendronate) and reduced the effect of alendronate on resorption (NTx) as well (-52% vs. -61%; P < 0.05, combination vs. alendronate). MK-677 plus alendronate increased BMD at the femoral neck (4.2% vs. 2.5% for alendronate; P < 0.05). However, similar enhancement was not seen with MK-677 plus alendronate in BMD of the lumbar spine, total hip, or total body compared with alendronate alone. GH-mediated side effects were noted in the groups receiving MK-677, although adverse events resulting in discontinuation from the study were relatively infrequent. In conclusion, the anabolic effect of GH, as produced through the GH secretagogue MK-677, attenuated the indirect suppressive effect of alendronate on bone formation, but did not translate into significant increases in BMD at sites other than the femoral neck. Although the femoral neck is an important site for fracture prevention, the lack of enhancement in bone mass at other sites compared with that seen with alendronate alone is a concern when weighed against the potential side effects of enhanced GH secretion.     

Short-term changes in bone turnover markers and bone mineral density response to parathyroid hormone in postmenopausal women with osteoporosis

CONTEXT: Treatment of osteoporotic women with PTH increases biochemical markers of bone turnover, increases axial bone mineral density (BMD), and reduces fracture risk. OBJECTIVE: Our objective was to determine the relationship between levels of baseline turnover before PTH therapy and short-term changes in turnover during PTH therapy and subsequent changes in areal and volumetric BMD. DESIGN AND SETTING: We conducted a randomized, placebo-controlled trial at four academic centers. PATIENTS: Patients included 238 postmenopausal women with low hip or spine BMD. INTERVENTION: Subjects were randomized to sc PTH (1-84), 100 mug/d (119 women), for 1 yr. MAIN OUTCOME MEASURE: Bone turnover markers were measured in fasting blood samples collected before therapy and after 1 and 3 months. Areal and volumetric BMD at the spine and hip were assessed by dual-energy x-ray absorptiometry and quantitative computed tomography (QCT) after 1 yr of therapy. RESULTS: Among women treated with PTH alone, the relationships between baseline turnover and 1-yr changes in dual-energy x-ray absorptiometry and QCT BMD were inconsistent. Greater 1- and 3-month increases in turnover, particularly the formation marker N-propeptide of type I collagen, were associated with greater increases in areal BMD. When volumetric hip and spine BMD were assessed by QCT, greater short-term increases in turnover were even more positively associated with 1-yr increases in BMD. Each sd increase in the 3-month change of N-propeptide of type I collagen was associated with an a 21% greater increase in QCT spine trabecular BMD. CONCLUSIONS: Greater short-term changes in turnover with PTH therapy are associated with greater 1-yr increases in spine and hip BMD among postmenopausal osteoporotic women.     

Calcium, vitamin D, and parathyroid hormone status in young white and black women: association with racial differences in bone mass

The etiology of the racial disparity in bone mass and fracture rate is unknown. Since the PTH-vitamin D endocrine system is a major regulator of calcium metabolism and bone turnover, this cross-sectional study examined the relationship of radial and lumbar bone density to vitamin D metabolite and PTH concentrations and to calcium intake and excretion in 67 white and 70 black highly comparable, healthy, premenopausal women. Bone density at both radial and lumbar sites was higher in blacks than in whites. Serum 25-hydroxyvitamin D was slightly but not statistically significantly (P = 0.08), lower in blacks than in whites, but there were no racial differences in 1,25-dihydroxyvitamin D, PTH, or renal tubular maximum for reabsorption of phosphate. The mean 25-hydroxyvitamin D concentration in blacks was well within the normal range and was not associated with evidence of secondary hyperparathyroidism. There were no correlations of bone density to vitamin D or PTH concentrations. Although there were no racial differences in dietary intake of calcium and vitamin D or in sodium excretion, 24-h urinary calcium excretion was significantly lower in blacks than in whites, and calcium excretion was inversely associated with radial bone density. In contrast to previous reports, in healthy, normal weight, premenopausal black women there is no evidence of vitamin D deficiency or secondary hyperparathyroidism, suggesting that factors other than the vitamin D-PTH axis are responsible for racial differences in bone mass.     

Effect of whole-body vibration exercise on lumbar bone mineral density, bone turnover, and chronic back pain in post-menopausal osteoporotic women treated with alendronate

BACKGROUND AND AIMS: Exercise may enhance the effect of alendronate on bone mineral density (BMD) and reduce chronic back pain in elderly women with osteoporosis. The aim of this study was to determine whether whole-body vibration exercise would enhance the effect of alendronate on lumbar BMD and bone turnover, and reduce chronic back pain in postmenopausal women with osteoporosis. METHODS: Fifty post-menopausal women with osteoporosis, 55-88 years of age, were randomly divided into two groups of 25 patients each: one taking alendronate (5 mg daily, ALN) and one taking alendronate plus exercise (ALN+EX). Exercise consisted of whole-body vibration using a Galileo machine (Novotec, Pforzheim, Germany), at an intensity of 20 Hz, frequency once a week, and duration of exercise 4 minutes. The study lasted 12 months. Lumbar BMD was measured by dual energy X-ray absorptiometry (Hologic QDR 1500W). Urinary cross-linked N-terminal telopeptides of type I collagen (NTX) and serum alkaline phosphatase (ALP) levels were measured by enzyme-linked immunosorbent assay and standard laboratory techniques, respectively. Chronic back pain was evaluated by face scale score at baseline and every 6 months. RESULTS: There were no significant differences in baseline characteristics, including age, body mass index, years since menopause, lumbar BMD, urinary NTX and serum ALP levels, or face scale score between the two groups. The increase in lumbar BMD and the reduction in urinary NTX and serum ALP levels were similar in the ALN and ALN+EX groups. However, the reduction in chronic back pain was greater in the ALN+EX group than in the ALN group. CONCLUSIONS: The results of this study suggest that whole-body vibration exercise using a Galileo machine appears to be useful in reducing chronic back pain, probably by relaxing the back muscles in post-menopausal osteoporotic women treated with alendronate.     

Three-year experience with alendronate treatment in postmenopausal osteoporotic Japanese women with or without type 2 diabetes

Aims

The increased risk of fractures in patients with type 2 diabetes can partly be explained by poor bone quality and extra-skeletal factors. A retrospective study was conducted to compare the outcome of alendronate (ALN) treatment for 3 years in postmenopausal osteoporotic Japanese women with or without type 2 diabetes.

Methods

One-hundred and fifty-one postmenopausal osteoporotic Japanese women (mean age at baseline: 67.8 years) who had been treated with ALN for more than 3 years in our outpatient clinic were analysed. The lumbar spine bone mineral density (BMD) was measured using dual energy X-ray absorptiometry, and the urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX) and the serum levels of alkaline phosphatase (ALP) were monitored during the 3-year treatment period. The incidence of osteoporotic fractures was also assessed.

Results

Sixteen women had type 2 diabetes and were receiving pharmacological treatment, and 135 were non-diabetic. The urinary NTX and serum ALP levels significantly decreased and the lumbar spine BMD significantly increased, compared with the baseline values, without causing any severe adverse events including osteonecrosis of the jaw, femoral diaphysis atypical fractures, and atrial fibrillation, in a manner that was similar among women with type 2 diabetes and non-diabetics. However, the incidence of non-vertebral fractures was significantly higher among women with type 2 diabetes than among the non-diabetics.

Conclusions

ALN treatment appeared to have the similar effect on surrogate markers in postmenopausal osteoporotic Japanese women with or without type 2 diabetes. Because of lacking in statistical power for fracture incidence due to the small sample size, further studies are warranted to confirm the results of the fracture incidence.     

T淋巴细胞参与调节甲状旁腺激素对骨代谢的作用

骨免疫学是研究骨代谢和免疫学之间相互作用的交叉学科,骨髓中T淋巴细胞参与了调节骨代谢的一系列反应。近年来,动物实验及临床试验结果提示:T淋巴细胞不仅可以直接分泌促进骨吸收和骨形成的细胞因子,还可以通过参与调节核因子κB受体活化因子配体(receptor activator of NF-κB ligand,RANKL)/骨保护素(osteoprotegerin, OPG)、 Wnt等信号通路,调节骨髓基质细胞对甲状旁腺激素(parathyroid hormone,PTH)的反应,从而影响PTH的作用。本文回顾近年来的研究结果,就T淋巴细胞参与调节PTH相关作用做一综述。     

Increases in bone mineral density after discontinuation of daily human parathyroid hormone and gonadotropin-releasing hormone analog administration in women with endometriosis

Intermittent PTH administration increases spinal bone mineral density (BMD) and prevents bone loss from the hip and total body in young women treated with a long acting GnRH analog for endometriosis. To establish whether these beneficial effects on BMD persist after PTH administration is discontinued, we remeasured BMD and biochemical markers of bone turnover in 38 women with endometriosis who had been treated with a GnRH analog alone (nafarelin acetate; 200 microg, intranasally, twice daily; n = 23; group 1) or who had received nafarelin plus human PTH-(1-34) (40 microg/day, s.c.; n = 15; group 2) for 6-12 months 1 yr after therapy was completed. Cyclic menstrual function returned promptly after nafarelin therapy was discontinued. In group 1, BMD increased significantly at all sites [P < 0.001 for the anterior-posterior (AP) and lateral spine; P = 0.014 for the femoral neck; P = 0.004 for the trochanter], except the proximal radius (P = 0.065) and total body bone density (P = 0.069) after nafarelin therapy was stopped. In group 2, BMD increased significantly at the AP spine (P < 0.001), lateral spine (P = 0.012), femoral neck (P = 0.002), and trochanter (P = 0.029) after nafarelin therapy was stopped. BMD of the spine in the AP projection increased more in group 2 and than in group 1 after therapy was stopped (P = 0.045). Despite these increases after discontinuation of nafarelin therapy, BMD was still significantly below baseline values at the AP spine (P < 0.001) and femoral neck (P = 0.006) and tended to be lower than baseline values at the trochanter (P = 0.057) and total body (P = 0.101) at the end of the 1-yr follow-up period in group 1. In contrast, BMD was significantly above baseline values at the AP and lateral spine (P < 0.001) sites and was similar to baseline values at the other skeletal sites at the end of the 1-yr follow-up period in group 2. Bone turnover returned to baseline values in both groups when therapy was stopped. We conclude that the beneficial effects of PTH on bone persist in women who regain cyclic menstrual function. Although part of the increases in BMD are probably due to restoration of ovarian function, additional increases in BMD most likely represent a further anabolic effect of PTH on bone that is not detected until after PTH administration is stopped.