Risk of Calcium Oxalate Nephrolithiasis after Calcium or Combined Calcium and Calcitriol Supplementation in Postmenopausal Women

Although calcium supplementation can cause hypercalciuria, the risk of nephrolithiasis has been shown to decrease rather than increase among subjects who had a higher calcium intake. Hypercalciuria is also a well-established side effect of calcitriol administration. However, the risk of nephrolithiasis is not well defined. The present study was undertaken to prospectively determine the effect of calcium with or without calcitriol on physicochemical risk factors associated with calcium oxalate nephrolithiasis in Thai postmenopausal women with osteoporosis. Subjects consisted of 53 Thai women more than 10 years postmenopausal who were randomly allocated to receive 750 mg of calcium carbonate supplement alone (n= 28) or 750 mg of calcium carbonate plus 0.5 mg calcitriol (n= 25) daily. Mean ± SEM for age was 65.3 ± 1.1 years, body weight 53.5 ± 1.3 kg. Urine samples for biochemical assays were collected at baseline and 3 months after treatment. Supersaturation for calcium oxalate stone formation was assessed from the 24 h urine constituents by the Tiselius’s index, AP(CaOx). Three months of calcium supplement alone resulted in a modest, but not significant, increase in urinary calcium (baseline, 2.90 ± 0.43 mmol/day; after treatment 3.58 ± 0.54 mmol/day) with no change in urinary oxalate, citrate or magnesium. In contrast, calcium together with calcitriol caused a significant increase in urinary calcium (baseline, 2.87 ± 0.41 mmol/day; after treatment, 4.08 ± 0.57 mmol/day; p<0.05). No significant change in other urine constituents after treatment with calcium and calcitriol was detected. Therefore, AP(CaOx) did not significantly increase either after calcium alone (baseline, 1.17 ± 0.39; after treatment, 1.36 ± 0.28) or after calcium plus calcitriol (baseline, 1.09 ± 0.17; after treatment, 1.09 ± 0.19). However, after treatments, 12 subjects (23%) – 6 receiving calcium supplement alone and 6 receiving calcium plus calcitriol supplement – had high AP(CaOx) values (greater than the upper limit of 95% CI for AP(CaOx) derived from non-stone-forming Thai women). The post-treatment/baseline ratio was 3.21 ± 0.74 for urinary calcium, 1.01 ± 0.19 for urinary oxalate, and 2.23 ± 0.42 (median 1.15) for AP(CaOx). The post-treatment/baseline ratio of calcium, but not for urinary oxalate, had a significant correlation with the post-treatment/baseline ratio of AP(CaOx). Our findings suggest that the alteration in the risk of calcium oxalate nephrolithiasis based on urinary composition is related to the alteration in urinary calcium. The risk of calcium oxalate nephrolithiasis does not increase significantly after calcium or combined calcium and calcitriol supplement in the majority of postmenopausal women with osteoporosis. Received: 10 March 1999 / Accepted: 16 November 1999     

Long-Term Effects of Continuous Combined HRT on Bone Turnover and Lipid Metabolism in Postmenopausal Women

This study was undertaken to investigate the effect of 10 years of hormone replacement therapy (HRT) on bone turnover and lipid metabolism in postmenopausal women. The single-centre trial was initiated as a 1-year, double-masked, randomized, parallel-group study of continuous combined HRT with 2 mg 17b-estradiol and 1 mg norethisterone acetate administered once daily with or without 1 mg estriol. Following preliminary results which showed no difference between the addition and omission of estriol, patients continued on an open-label extension phase of continuous combined HRT without estriol for a further 9 years. Of the 52 women who entered the original double-masked study, 32 entered the open-label extension phase. The 10-year analysis was based on 27 patients. Major increases in bone mineral density (BMD) of the lumbar spine were seen during the first 3 years of treatment, remaining statistically significant compared with baseline at all visits throughout the 10-year follow-up (p40.025). Statistical modelling confirmed that there were no decreases in BMD after these initial increases. BMD remained 5.5% higher than baseline values after 10 years of continuous combined HRT. Mean total cholesterol levels were significantly reduced after 10 years of therapy (p= 0.012), with no significant changes in serum triglyceride and low-density lipoprotein (LDL)-cholesterol levels from baseline values at this time. High-density lipoprotein (HDL)-cholesterol levels, however, were reduced by 15.4% (p50.001). In conclusion, 10 years of continuous combined HRT resulted in a significant and sustained increase in BMD. This treatment regimen therefore appears to be well suited for the long-term prevention of osteoporosis in postmenopausal women. Received: 1 July 1997 / Accepted: 15 December 1997     

Identification of Early Postmenopausal Women with No Bone Response to HRT: Results of a Five-Year Clinical Trial

Hormone replacement therapy (HRT) prevents postmenopausal bone loss and fractures. However, the occurrence of women with no bone response to HRT has not been widely examined. We identified the densitometric nonresponders to long-term HRT and investigated some characteristics and biochemical variables as possible predictors of densitometric nonresponse in postmenopausal women. The study population was a subsample of the Kuopio Osteoporosis Study (n= 14.220). A total of 464 early postmenopausal women were randomized into four treatment groups: (1) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate); (2) vitamin D₃; (3) HRT + Vitamin D₃ combined; and (4) placebo. In this study, the data from HRT and placebo groups were analyzed. Lumbar (L2–4) and femoral neck bone mineral density (BMD) were determined by dual-energy X-ray absorptiometry (DXA) at baseline and after 5 years of treatment. A densitometric nonresponder was defined as a woman whose 5-year BMD change was similar to the mean BMD change (+ 95% CI) of the placebo group or worse. Altogether, 74 women in the HRT group and 104 women in the placebo group complied with the treatment. According to spinal BMD analysis, 11% of the women were classified as densitometric nonresponders; the corresponding proportion for femoral BMD analysis was 26%. Both smoking (p= 0.003) and low body weight (p= 0.028) were significant risk factors for densitometric nonresponse to HRT. After 6 months of treatment the densitometric nonresponders (hip) had a significantly higher mean serum follicle stimulating hormone (FSH) level (p= 0.038) and lower increases in serum estradiol levels (p= 0.006) than the densitometric responders. The mean changes in serum FSH and alkaline phosphatase levels were significantly lower among the densitometric nonresponders (spine) than responders (p= 0.043 and 0.017, respectively). In conclusion, this prospective study shows that especially current smokers and women with low body weight are at increased risk of poor bone response to HRT. Repeated serum FSH, estradiol and alkaline phosphatase measurements during the first months of long-term HRT may be helpful in identifying the women with no bone response to HRT. Received: 29 January 1999 / Accepted: 2 August 1999     

The Response to Calcitriol Therapy in Postmenopausal Osteoporotic Women is a Function of Initial Calcium Absorptive Status

Calcitriol is used in the treatment of osteoporosis but the indications for its use have not been clearly defined. Because it stimulates calcium absorption, we have tended to select osteoporotic patients with low calcium absorption for this therapy and now report the results. We measured the hourly fractional rate of calcium absorption (α) with ⁴⁵Ca and fasting urinary calcium/creatinine (Ca/Cr) and hydroxyproline/creatinine (OHPr/Cr) in 103 postmenopausal women aged 68 (0.67SE) years with vertebral compression fractures (77) or forearm or vertebral bone density below the young normal range (26). They were given 0.25 μg daily of calcitriol (Rocaltrol, Roche, Basle, Switzerland) with a 1 g calcium supplement daily for 6–12 weeks, when the biochemical tests were repeated. Initial OHPr/Cr was inversely related to initial α (P= 0.001) and positively to initial Ca/Cr (P < 0.001). α rose on therapy from 0.47 (0.018) to 0.59 (0.018) per hour (P < 0.001) and OHPr/Cr fell in the whole group from 19.1 (0.83) to 13.8 (0.58) (P < 0.001). The change in α on therapy (corrected for the ``regression to the mean effect') was inversely related to initial α (P < 0.001) as was the change in OHPr/Cr (P= 0.001). There was no relationship, however, between initial Ca/Cr and either the rise in α or the fall in OHPr/Cr on therapy. The data support the concept that low calcium absorption is a cause of negative calcium balance in postmenopausal osteoporosis and that the effectiveness of calcitriol therapy is inversely related to the initial rate of calcium absorption. Received: 16 August 1996 / Accepted: 5 March 1997     

A Comparison of Continuous Alendronate, Cyclical Alendronate and Cyclical Etidronate with Calcitriol in the Treatment of Postmenopausal Vertebral Osteoporosis: A Randomized Controlled Trial

A number of drugs are now available for the treatment of established osteoporosis and have been shown to significantly increase bone mineral density (BMD). There are, however, few comparative treatment studies and, furthermore, adverse events remain a problem with some of the newer agents, particularly in the elderly, in everyday clinical practice. We report a 12 month, open labeled, randomized controlled, prospective treatment study in 140 postmenopausal women with established vertebral osteoporosis, comparing the effect of continuous alendronate, cyclical alendronate and cyclical etidronate with calcitriol in terms of gain in BMD, reduction in bone turnover markers and adverse event profile. The mean percentage increases in BMD at 12 months, at the spine and hip respectively, were: continuous alendronate 5.7%, 2.6%; cyclical alendronate 4.1%, 1.6%; cyclical etidronate 4.9%, 2.0% (p<0.01) and calcitriol 2.0%, 0.4% (NS). In comparison with calcitriol, the mean changes in BMD at the spine and hip respectively were greater in the other groups; continuous alendronate: 3.7% (95% CI 1.4 to 8.3), 2.2% (95% CI 0.7 to 4.0); cyclical alendronate: 2.1% (95% CI 1.2 to 6.4), 1.2% (95% CI −0.3 to 3.0); cyclical etidronate: 2.9% (95% CI 1.9 to 6.5), 1.6% (95% CI 0.9 to 3.1)). The reduction in bone turnover markers was between 26% and 32% in the alendronate and etidronate groups (p<0.01), with a trend toward greater reduction in the continuous alendronate group. Eight patients discontinued the study: 6 in the continuous alendronate group, 1 in the cyclical alendronate group and 1 in the calcitriol group. Two patients in the cyclical etidronate group were unable to tolerate the Cacit component, but continued on substituting Cacit with Calcichew. In summary, 12 months of treatment with continuous alendronate, cyclical alendronate and cyclical etidronate are effective in terms of the gain in BMD at the anteroposterior spine and total hip in a comparable treatment population. These treatments are more effective than calcitriol and were generally well tolerated. Continuous alendronate showed a trend toward a larger gain in BMD and greater suppression of bone turnover markers than the other treatment groups, but had a higher incidence of adverse events, particularly within the older subgroup. Cyclical alendronate offers a lower adverse event profile and appears to be effective in comparison with continuous treatment, and may possibly be an alternative in the elderly. However, further studies are necessary, but more importantly with fracture end-points. Received: 6 April 1999 / Accepted: 8 June 2000     

Relationships Between Intestinal Calcium Absorption,Serum Vitamin D Metabolites and Smoking in Postmenopausal Women

Smoking has been associated with low bone density, fractures and poor intestinal calcium absorption. Calcium absorption is a critical factor in calcium balance in postmenopausal women but the mechanisms causing decreased absorption efficiency in postmenopausal smokers are controversial and poorly defined. We performed a cross-sectional study of 405 postmenopausal women attending a clinic for the management of osteoporosis to compare intestinal calcium absorption efficiency, serum vitamin D metabolites and parathyroid hormone levels in postmenopausal women who had never smoked, who were smokers previously or who were current smokers, to examine the relationships between these variables in smokers. Two hundred and fifty-two of the women had never smoked, 79 had smoked previously and 74 were current smokers. The hourly fractional rate of calcium absorption was similar in non-smokers and those who had previously smoked. Radiocalcium absorption was less in the 74 smokers compared with the 331 non-smokers [0.60 (0.29 SD) vs 0.71 (0.27); p= 0.004], as were serum calcitriol (p<0.001) and parathyroid hormone (PTH) (p<0.01). There was no difference in the relationship between calcium absorption and serum calcitriol between smokers (r= 0.38) and non-smokers (r= 0.28); hence the impaired calcium absorption in the smokers was almost entirely attributable to suppression of the PTH–calcitriol endocrine axis. In postmenopausal women smoking is associated with a reduction in calcium absorption efficiency due to suppression of the PTH–calcitriol axis. This impairment of calcium absorption could lead to accelerated bone loss and limit the usefulness of dietary calcium supplementation. Received: 21 May 2001 / Accepted: 4 September 2001     

Calcium and Vitamin D Supplementation Increases Spinal BMD in Healthy, Postmenopausal Women

We undertook a double-masked, randomized, placebo-controlled trial to evaluate the effect of a calcium and vitamin D supplement and a calcium supplement plus multivitamins on bone loss at the hip, spine and forearm. The study was performed in 240 healthy women, 58–67 years of age. Duration of treatment was 2 years. Bone mineral density (BMD) was measured at the lumbar spine, hip and forearm. A dietary questionnaire was administered twice during the study and revealed a fairly good calcium and vitamin D intake (919 mg calcium/day; 3.8 mg vitamin D/day). An increase in lumbar spine BMD of 1.6% was observed in the treatment group after 2 years (p50.002). In the placebo group no significant changes were observed during the 2 years. Lumbar spine BMD was significantly higher in the treatment group at both 1 (p50.01) and 2 years (p50.05) compared with the placebo group. Though not significant, the same trend was seen at the hip. No significant changes from baseline values were observed at the distal forearm in either the treatment or the placebo group. In conclusion, we found a significant increase in urinary calcium excretion in the treatment group compared with the placebo group. Together with significant changes in serum calcium and serum parathyroid hormone, this indicates that a long-term calcium and vitamin supplement of 1 g elementary calcium (calcium carbonate) and 14 mg vitamin D₃ increases intestinal calcium absorption. A positive effect on BMD was demonstrated, even in a group of early postmenopausal age, with a fairly good initial calcium and vitamin D status. Received: 2 July 1997 / Accepted: 28 October 1997     

Absorption of Calcium as the Carbonate and Citrate Salts, with Some Observations on Method

Calcium supplement use has increased and there is confusion about the relative absorbability of various sources. Absorbability of calcium from the carbonate and citrate salts was compared at 300 mg and 1000 mg calcium loads, ingested as part of a light breakfast meal. Absorption was measured at the high load both by tracer appearance in serum and by the absorptive increment in urinary calcium, and at the low load by the tracer method only. Subjects were 37 healthy adult men and women, studied as outpatients, and each tested on both salts at the same load. Mean tracer absorption (± SD) for both salts combined was 36.0% at the 300 mg load and 28.4% at the 1000 mg load. In both experiments the observed mean difference in absorption between salts was very small. By the tracer method the within-subject difference (carbonate less citrate) was +3.3%± 1.2% of the ingested dose (mean ± SEM; P <0.05) at the high load, and at the low load, 3.6%± 2.7% (NS). Combining the two experiments yielded zero difference between sources. By the urinary calcium increment method, the mean difference between salts at the 1000 mg load was 1.8 ± 4.1 mg (NS). Side-by-side comparisons of the two methods revealed that the tracer method was 3 times more sensitive than the urinary increment method. We conclude that, when taken with food, calcium from the carbonate salt is fully as absorbable as from the citrate, and that the urinary increment method is not sufficiently sensitive to be useful in comparing sources in free-living subjects. Received: 6 April 1998 / Accepted: 6 April 1998     

Attitudes to Osteoporosis and Hormone Replacement Therapy among Elderly Women

This study compares the attitudes toward osteoporosis and its treatment between a group of elderly women admitted to hospital for therapy of an osteoporotic fracture and a control group admitted for joint replacement surgery. We surveyed 97 women (64 with a fracture, and 33 controls) and found that the two groups of patients demonstrated a similar risk factor profile for osteoporosis and poor knowledge of osteoporosis and its available treatments, including hormone replacement therapy (HRT). By selecting a control group of women with no recent fracture, we hoped to highlight the effect of sustaining a recent fracture on attitudes to treatment. Initially only 10% (8 in the fracture group and 2 in the control group) were interested in treatment for osteoporosis, but those women who had been admitted with a fracture were significantly more receptive to education about osteoporosis and to the offer of further investigation and treatment of osteoporosis (38 versus 10, p= 0.007). We conclude that it is worthwhile offering education, screening and treatment to elderly patients who present with a fracture. Received: 11 June 1997 / Accepted: 6 April 1998     

Cost-Effectiveness of Hormone Replacement Therapy for Fracture Prevention in Young Postmenopausal Women: An Economic Analysis Based on a Prospective Cohort Study

A recent systematic review of randomized controlled trials has shown that hormone replacement therapy (HRT) prevents fractures when taken soon after the menopause. HRT for treatment of menopausal symptoms is relatively cost-effective, but whether its use for prevention of perimenopausal fractures is economically efficient is unknown. We undertook a 6-year follow-up of 3645 perimenopausal women who had a bone mineral density (BMD) measurement with recommendation to use HRT if low BMD was present. Data were collected on incident fractures and costs. After an average of 6.2 years of follow-up HRT use significantly reduced incident fractures by 52% (95% CI: 67% to 18%). However, costs were increased by an average of ￡275 (95% CI: ￡228 to ￡330) for the group as a whole; for hysterectomized women costs were increased less (￡138), but this was still significantly greater than for non-HRT users (95% CI: ￡6 to ￡275). The cost per averted fracture was about ￡11 000 (95% CI: ￡8625 to ￡13 872) for the whole group and for hysterectomized women the corresponding figure was substantially less (￡1784; 95% CI: ￡59 to ￡3532). HRT given to women at or shortly after the menopause is therefore associated with a halving of fracture incidence. Such a policy for hysterectomized women without menopausal symptoms may be cost-effective as such women are at elevated risk of fracture and need cheaper, unopposed, estrogens. Received: 23 October 2001 / Accepted: 13 February 2002     

Comparison of Calcitriol Treatment with Etidronate–Calcitriol and Calcitonin–Calcitriol Combinations in Turkish Women with Postmenopausal Osteoporosis: A Prospective Study

Calcitriol has been widely used in the management of osteoporosis, but its efficiency is a matter of controversy. It is not known whether combinations of calcitriol and antiresorptive agents such as etidronate and calcitonin are superior to calcitriol alone in the treatment of postmenopausal osteoporosis. To make this determination, 30 Turkish women with postmenopausal osteoporosis between 45 and 68 years of age were randomized to receive either intermittent cyclical etidronate (400 mg/day, for 14 days) followed by 60 days of cyclical calcitriol therapy 0.25 μg twice daily (group 1; n= 10), or calcitriol 0.25 μg twice daily (group 2; n= 10), or calcitriol 0.25 μg/day in combination with 100 IU intranasal salmon calcitonin taken every other day (group 3; n= 10) through a 1-year period. Bone mineral density (BMD) of lumbar spine (L2 to L4) was determined for each patient by dual-photon absorptiometry (¹⁵³Gd) at baseline, after 6 months, and at the end of the study. There was no significant difference among groups with respect to mean spinal BMD at baseline, after 6, and after 12 months. No significant spinal BMD changes occurred in any group from baseline, after 6 months, and after 12 months. Four patients in groups 1 and 2 and five patients in group 3 developed hypercalcemia at least once during therapy. Hypercalciuria occurred at least once in 9, 10, and 7 patients in groups 1, 2, and 3, respectively. One patient in group 2 developed a renal stone at the end of the study. Mean urine hydroxyproline levels did not change significantly in any group with respect to baseline. The data suggest that one-year treatment with calcitriol, given either alone or in combination with antiresorptive agents, does not improve spinal BMD in Turkish women with postmenopausal osteoporosis, and is associated with a high rate of adverse events. Received: 4 October 1996 / Accepted: 31 December 1996     

Hand Ultrasound for Osteoporosis Screening in Postmenopausal Women

There is a need for low-cost screening methods to detect low bone mass (osteopenia or osteoporosis) in postmenopausal women. The utility of quantitative ultrasonography (QUS) of the hand was assessed for osteoporosis screening using the WHO criteria. Bone mineral density (BMD) was measured in 206 postmenopausal Mexican-American women at the total hip and lumbar spine by dual-energy X-ray absorptiometry (DXA). The amplitude-dependent speed of sound (AD-SoS) was measured in the phalanges by QUS. Subjects identified by DXA as having osteopenia or osteoporosis had significantly lower AD-SoS values in comparison with normals. Estrogen users had significantly higher spine and hip BMD and AD-SoS values compared with non-estrogen users. The areas under the receiver operating characteristic (ROC) curves (AUC) for AD-SoS to screen for osteoporosis (T-score ≤−2.5) at the spine or hip were 0.73 for all subjects, 0.74 for estrogen users and 0.68 for non-estrogen users. The AUC for non-estrogen users to screen for osteopenia (T-score −1 to −2.5) was 0.77. Performance comparisons of AD-SoS with SCORE (a risk factor questionnaire) and body weight showed AUC values of 0.73, 0.69 and 0.65, respectively. QUS was the superior screening test when considering both the AUC and the shape of the ROC curves. For non-estrogen users, the group at higher risk for osteoporosis, QUS correctly identified 31% as normal, and 62% as having low bone mass and needing DXA referral; and the remaining 7% were false negatives. These data suggest phalangeal QUS can be effectively used for screening osteoporosis in postmenopausal women. Received: 2 April 1998 / Accepted: 27 July 1999     

Ultrasound Measurements of Proximal Phalanges in Polish Early Postmenopausal Women

The aim of this cross-sectional study was to evaluate skeletal status in Polish early postmenopausal women using ultrasound measurement at the proximal phalanges of the hand. We assessed the ability of the method to discriminate between healthy and osteoporotic individuals, the influence of age and menopause on ultrasound values, the impact of hormone replacement therapy and the relationships between ultrasound measurement and type of fracture. Five hundred and three early postmenopausal women were divided into three groups: (1) healthy (n= 398, mean age 53.4 years), (2) fractured (n= 43, mean age 53.9 years), (3) treated with estrogens (n= 62, mean age 53.5 years). Groups were matched for age and years since menopause (YSM). Group 2 was subdivided into those with and without wrist fracture. No drugs except estrogens were used by the subjects studied and no diseases known to affect bone metabolism were observed. Bone status was assessed by a DBM Sonic 1200 (Igea, Italy), a device that measures amplitude-dependent speed of sound (AD-SoS) at the proximal phalanges II–V of the hand. AD-SoS had the highest value in estrogen-treated women (1996.5 ± 66.5 m/s), the lowest in fractured persons (1883.6 ± 77.1 m/s) and a medium value in healthy women (1949.2 ± 78.0 m/s). All values were significantly different from each other (p <0.0001). AD-SoS values for the subgroups of group 2 were 1873.0 ± 80.6 m/s for those with wrist fracture and 1914.0 ± 73.0 m/s for those without; they were not statistically different. The hypothesis that AD-SoS at the proximal phalanges might be more sensitive to wrist fracture was not confirmed by Fisher's exact test for frequencies. Linear regression showed age-related changes, with r values –0.4 (p <0.00001), –0.47 (p <0.005), –0.37 (p <0.005), and YSM-related changes, with r values of –0.44 (p <0.00001), –0.32 (p <0.005), and –0.18 (NS) in groups 1, 2 and 3, respectively. It is concluded that: (1) ultrasound measurements of the proximal phalanges were able to discriminate between healthy and osteoporotic individuals; (2) the method is useful in detecting age and postmenopause-related changes within the skeleton; and (3) hormone replacement therapy significantly reduced the impact of the menopause on bone loss as detected by ultrasound. Received: 28 February 1997 / Revised: 4 March 1998     

Therapy of Established Postmenopausal Osteoporosis with Monofluorophosphate plus Calcium: Dose-Related Effects on Bone Density and Fracture Rate

Recent experience from different groups suggests that low fluoride doses resulting in moderate increases in bone mineral density (BMD) may be advantageous in terms of fracture-reducing potency. In a randomized prospective 3-year study we examined the therapeutic efficacy of different dosages of monofluorophosphate (MFP) plus calcium in comparison with calcium alone in 134 women with established postmenopausal osteoporosis (mean age 64.0 years, average vertebral fractures per patient 3.6). Group A received 1000 mg calcium/day and a low-dose intermittent MFP regimen (3 months on, 1 month off) corresponding to an average daily fluoride ion dose of 11.2 mg. Group B received 1000 mg calcium/day plus continuous MFP corresponding to 20 mg fluoride ions per day. Group C was treated with 1000 mg calcium alone throughout the study period. Bone density was measured with dual-energy X-ray absorptiometry at L2–4 and three proximal femur areas and with single photon absorptiometry at two radius sites. New vertebral fractures were identified from annual lateral radiographs of the spine. A significant reduction in subjective complaints as measured by a combined pain–mobility score (CPMS) was found in both fluoride groups in comparison with the calcium monotherapy group. Group A showed increases in BMD at all six measuring sites, reaching +12.6% at the spine after 3 years. In group B we found significant increases at the spine, Ward’s triangle and distal radius, but slight decreases at the femoral neck and radius shaft. For the spine the average change amounted to +19.5% after 3 years. In group C losses of BMD were observed at all six sites, with an average loss of 1.6% for the spine at the end of the study. The incidence of new vertebral fractures per 100 patient-years was 8.6, 17.0 and 31.6 in groups A, B and C, respectively. In conclusion, both calcium–MFP regimens resulted in significantly lower vertebral fracture rates than calcium monotherapy. However, the low intermittent MFP regimen, leading to a mean annual increase in spinal BMD of only 4.2%, showed a clear trend to greater effectiveness in reducing vertebral fracture than the higher fluoride dosage that was followed by an average spinal BMD increase of 6.5% per year. Furthermore the rate of fluoride-specific side effects (lower-extremity pain syndrome) was 50% lower in patients receiving the lower fluoride dosage. Received: 3 November 1997 / Accepted: 4 June 1998     

Treatment of Reduced Bone Mineral Density in Athletic Amenorrhea: A Pilot Study

There is considerable concern about the adverse effects on the skeleton of loss of menstrual function as a result of athletic activity, as well as uncertainty as to how it should be managed clinically. In a pilot intervention study 34 elite middle and long-distance runners, aged 18–35 years, with menstrual irregularity due to their athletic activity were randomized to three groups: (A) to receive hormone replacement therapy (HRT) and 1000 mg calcium per day (n= 10), (B) to receive 1000 mg calcium per day (n = 14), (C) a control group who received no treatment (n= 10). Bone mineral density (BMD) was measured in the left hip and lumbar spine (L2–4) using dual-energy X-ray absorptiometry. Results were first analyzed according to whether menstruation returned, either naturally or secondary to HRT (EU), and compared with those from subjects who remained amenorrheic (AM). During the first year BMD increased in the EU group in Ward’s triangle (3.8%) and the lumbar spine (4.1%; both P<0.05). BMD fell in the AM group in all regions and the between-group differences were 5.6% (p<0.02) in Ward’s triangle, 5.8% (p<0.02) in L2–4 and 3.9% in the trochanter (p<0.05). An ‘intention to treat’ analysis was then performed. It was found that the mean relative improvement at 1 year in spinal BMD was only 1.5%, due to return of menses in some of the controls and withdrawals from treatment in the treatment group. In consequence, a trial designed to show, with 80% power and 5% significance, a measurable benefit in lumbar spine BMD resulting from allocation to HRT treatment would require about 1150 athletes with amenorrhea or oligomenorrhea. These numbers could be reduced substantially to 380 subjects by confining the trial to completely amenorrheic athletes, who in this study were less likely to regain menses. For these and other logistical reasons, an HRT trial in amenorrheic athletes could only be successfully organized through international collaboration. This study illustrates the major effects of treatment withdrawals and instability of menstrual status on the design of longitudinal studies on the bony effects of menstrual dysfunction prior to menopause. Received: 5 August 1998 / Accepted: 11 March 1999     

The Long-Term Effectiveness of Preventive Strategies for Osteoporosis in Postmenopausal Women: A Modeling Approach

Based on data from the literature, we have developed a computer-based simulation model to compare the long-term effectiveness of different preventive strategies of osteoporotic fractures. The Markov model comprises 25 states, including states which describe women distributed according to three levels of fracture risk, fractures states, post-fracture states and a death state. We chose eight standard preventive strategies, which we compare with the ‘No Treatment’ reference strategy. The first two strategies consist in treating all 50-year-old women for 5 or 10 years with hormone replacement therapy (HRT). Strategies 3 and 4 aim at assessing a 5-year course of treatment with bisphosphonates in osteopenic and osteoporotic 65- or 75-year-old women. Strategies 5 and 6 combine 5 years of HRT in all 50-year-old women with 5 years of bisphosphonates in osteopenic and osteoporotic women at 65 or 75 years. The last two strategies simulate 10 years of HRT in all 50-year-old women, followed by strategy 3 or strategy 4. Simulated life expectancy and mean ages of fracture occurrence fit well with the observed data. All the preventive strategies tested reduced the number of fractures. Early 10-year HRT in all women, plus 5 years of bisphosphonates in women at risk of fractures at 65 or 75 years, are the most effective strategies, with an 18.4–19.0% reduction in all fractures, and a 25.6–26.1% reduction in the number of hip fractures. Strategy 2 has a similar outcome, thus demonstrating the value of treatment started early and sustained over a long period. The strategies implemented later, S3 and S4, only concern women at risk (i.e., osteopenic or osteoporotic), and are less effective, with a 1.5–2.1% decrease in all fractures. The combined strategies, S5 and S6, produce intermediate results: a 12.9–13.5% reduction in the number of all fractures and a 17.5–17.9% reduction in hip fractures. Received: 11 February 1999 / Accepted: 9 December 1999     

Prevalence of Osteoporosis by Educational Level in a Cohort of Postmenopausal Women

To evaluate whether the prevalence of osteoporosis and related risk factors might be influenced by the level of education, as has been demonstrated for many other chronic diseases, 6160 postmenopausal women at their first densitometric referral were interviewed about reproductive variables, past and current use of estrogens, prevalence of chronic diseases, and lifestyle factors such as calcium intake, physical activity, smoking and overweight. This sample was stratified by years of formal education. Densitometric evaluation was performed by dual-energy X-ray absorptiometry. Age at menarche, past exposure to oral contraceptives, use of hormone replacement therapy, prevalence of chronic diseases, physical activity, overweight and smoking showed significant trends according to the years of education. The prevalence of osteoporosis showed an inverse relationship with level of education, ranging from 18.3% for the most educated to 27.8% for the least educated women. Multiple logistic regression analysis demonstrated a predictive role toward osteoporosis by age, age at menarche and menopause, hormone replacement therapy, calcium intake, physical activity and body mass index. Using the lowest educational level as reference category, increases in educational status were associated with a significantly reduced risk for osteoporosis (OR = 0.76, 95% CI 0.65–0.90 for 6–8 years of schooling; OR = 0.68, 95% CI 0.57–0.82 for 9 years or more). This study shows differences in the prevalence of osteoporosis among educational classes and the protective role played by increases in formal education. If these results are confirmed in other population studies, public health intervention programs will have to consider the socioeconomic and cultural background of the population strata that run a greater risk of osteoporosis. Received: 7 March 1998 / Accepted: 9 July 1998     

Fractal Analysis of Trabecular Bone Texture on Radiographs: Discriminant Value in Postmenopausal Osteoporosis

Trabecular bone microarchitecture cannot be routinely evaluated. We have developed and validated a fractal analysis of trabecular bone texture on calcaneus radiographs. The aim of this work was to evaluate the ability of the fractal analysis to discriminate a group of 39 postmenopausal women with osteoporotic (OP) vertebral crush fractures (68.0 + 10.8 years) from an age-matched control group of 39 women (68.0 + 10.7 years). The value of the fractal analysis was compared with the value of the femoral neck bone mineral density (FNBMD) and trochanteric bone mineral density (TRBMD). The result is expressed by the parameter H_{me an} (H_{me an}= 2 7 fractal dimension). H_{me an} value was 0.691 + 0.050 in the OP group versus 0.739 + 0.024 in the controls, while FNBMD was 0.598 + 0.113 g/cm² versus 0.645 + 0.109 g/cm² and TRBMD was 0.512 + 0.108 g/cm² versus 0.594 + 0.106 g/cm² respectively. The statistical significance of the H_{me an} test (p50.0001) was higher than for FNBMD (p50.05) and for TRBMD (p= 0.0004). We used a receiver operating characteristic (ROC) curve to check this superiority. The area under the ROC curve was 0.824 for H_{me an}, 0.633 for FNBMD and 0.727 for TRBMD. This superiority of the H_{me an} ROC curve was statistically significant versus FNBMD, but not versus TRBMD. In a second analysis, we studied the subgroups of OP patients and controls with overlapping FNBMD or TRBMD values to check whether the fractal dimension test could be discriminant in these subgroups. Significant statistical differences were found for H_{me an} between OP patients and controls in the overlapping subgroup for FNBMD or TRBMD (respectively p= 0.006 and p50.02). These data confirm that the fractal analysis of texture on calcaneus radiographs is able to discriminate OP patients with vertebral crush fracture from controls. This discrimination was stronger than that obtained by FNBMD or TRBMD alone. It was also present when we compared subgroups with overlapping values of FNBMD or TRBMD. Received: 9 Sepember 1997 / Revised: 6 April 1998     

Unbalanced Diet to Lower Serum Cholesterol Level is a Risk Factor for Postmenopausal Osteoporosis and Distal Forearm Fracture

The purpose of this study was to assess whether dietary changes aimed at reducing serum cholesterol can increase the risk of osteoporosis (OP) and fracture. The study group consisted of 311 postmenopausal women with high serum cholesterol levels and following a diet low in dairy products (calcium intake estimated at less than 300 mg/day) for 27.3 ± 29.1 months. This sample was compared with a case–control group of 622 healthy postmenopausal women paired for age and age at menopause and with a calcium intake estimated at more than 1 g/day. Bone mineral density was measured at the lumbar spine by dual-energy X-ray absorptiometry. Prevalence of OP was significantly higher in women with a low dairy calcium intake (42.1% vs 22.3%; p<0.0001), as was the number of Colles” fractures occurring after menopause (4.5% vs 1.6%; p = 0.008). Multiple logistic regression analyses demonstrated that a diet low in dairy calcium was a risk factor for OP (OR = 2.52, 95% CI 1.84–3.45) and Colles” fracture (OR = 2.72, 95% CI 1.18–6.26). In the low dairy calcium group, diet duration significantly influenced the risk of OP (OR = 1.13, 95% CI 1.01–1.25 for 1 year of diet). No differences in further risk factors for coronary heart disease were found between the groups, but the proportion of women physically active was lower in the women with high serum cholesterol levels. A diet that severely limits calcium intake from dairy products in an attempt to correct raised serum cholesterol levels is a risk factor for postmenopausal OP and Colles” fracture. Dietary intervention methods to lower serum cholesterol in postmenopausal women should maintain an adequate calcium intake by providing calcium from low-fat dairy products or calcium supplements. Received: 16 May 2000 / Accepted: 18 November 2000     

Biochemical Variables in Pre- and Postmenopausal Women: Reconciling the Calcium and Estrogen Hypotheses

There is controversy as to whether the rise in urinary calcium at the menopause is the cause or the result of the rise in bone resorption at that time. In an attempt to resolve this issue, we have compared the relevant biochemical variables in 102 premenopausal volunteers (mean age 37 years; range 21–52) and 86 apparently normal postmenopausal women (mean age 55 years; range 40–60). We measured the fasting serum calcium, creatinine, proteins, electrolytes and intact parathyroid hormone (PTH), and the urinary calcium and creatinine both after an overnight fast and in a 24-h collection. We calculated serum calcium fractions, creatinine clearance and the notional tubular maximum reabsorptive capacity for calcium. Creatinine excretion and clearance were lower in the post- than in the premenopausal women after correction for surface area and age. Total serum calcium was higher in the post- than in the premenopausal women but this was accounted for by the higher ligand concentrations in the former. Fasting and 24-h urinary calcium were also higher in the post- than in the premenopausal women due in part to the former’s higher filtered load of calcium (due to their higher serum complexed calcium) but mainly to their reduced tubular reabsorption of calcium despite their slightly raised serum PTH. Our analysis resolves the rise in urinary calcium at the menopause into its two components: increased filtered load and reduced tubular reabsorption. The changes in these two variables, neither of which can be attributed to increased bone resorption, produce an increase in calcium requirement that is sufficient to account for postmenopausal bone loss. However, the translation of this menopausal increase in calcium requirement into an increase in bone resorption at near-normal serum PTH levels requires some menopause-dependent change in the responsiveness of the bone to calcium demand. We suggest that this change may occur at the level of the osteoclasts and that estrogen may modify the calcium feedback setpoint in these cells in a manner analogous to calcitonin. This model resolves the apparent conflict between the estrogen and calcium hypotheses and explains the synergism between these two treatment modalities. Received: 8 June 1998 / Accepted: 5 September 1998