Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism

Estrogen replacement therapy (ERT) decreases total serum calcium by about 0.5 mg/dl in postmenopausal women with primary hyperparathyroidism (PHPT). We investigated the ability of raloxifene, which has skeletal antiresorptive properties similar to those of ERT, to decrease serum calcium concentrations and markers of bone turnover in PHPT. Eighteen postmenopausal women with asymptomatic PHPT were randomized to 8 wk of raloxifene (60 mg/d) or placebo, followed by a 4-wk washout. At baseline, the groups were well matched. The calcium concentration decreased significantly by 8 wk of raloxifene administration (10.8 +/- 0.2 to 10.4 +/- 0.2 mg/dl; P < 0.05), as did markers of bone resorption and formation [osteocalcin, 11.4 +/- 1.6 to 9.9 +/- 1.6 nmol/liter (P < 0.05); serum N-telopeptide, 21.2 +/- 3.4 to 17.3 +/- 2.8 nmol bone collagen equivalents/liter (P < 0.05)]. Four weeks after raloxifene was discontinued, indices were indistinguishable from baseline. Raloxifene administration did not affect serum PTH, 1,25-dihydroxyvitamin D, total alkaline phosphatase, or urinary calcium excretion. Calcium and bone marker changes were therefore similar to those observed with ERT in PHPT. This short-term study suggests that raloxifene may be a useful approach to the treatment of postmenopausal women with mild PHPT.     

Between-meal risedronate does not alter bone turnover in nursing home residents

OBJECTIVES: To assess the effect of between-meal weekly risedronate and daily calcium 630 mg and vitamin D 400 IU on bone turnover markers. DESIGN: Randomized,double-blind,placebo-controlled trial. SETTING: Skilled nursing home (NH). PARTICIPANTS: Sixty skilled-NH residents (46 men, 14 women), mean age+/-standard deviation of 76+/-6, were randomized to receive risedronate 30 mg (n=31) or matching placebo (n=29) once weekly for 12 weeks. All received 315 mg calcium with 200 IU vitamin D twice daily. MEASUREMENTS: Bone-specific alkaline phosphatase (BSAP), N-telopeptide of type 1 collagen (NTx), 25-hydroxyvitamin D (25OHD), and parathyroid hormone were measured at baseline and 6 and 12 weeks. RESULTS: Risedronate reduced BSAP significantly more than placebo (P<.05) at 6 weeks but not at 12 weeks; no treatment effect on serum NTx was observed. Defining hypovitaminosis D as a serum 25OHD concentration below 32 ng/mL, 50 of 53 (94%) study participants were low at baseline (mean 25OHD 19 ng/mL). Vitamin D levels remained insufficient in 74% of participants after 12 weeks. CONCLUSION: In this NH population, weekly risedronate administered using a between-meal dosing schedule reduced serum BSAP at 6 weeks of treatment; this effect was not observed at 12 weeks. The overall lack of change in bone turnover markers suggests that this risedronate dose and schedule would not be expected to increase bone density or reduce fracture risk in this population. Hypovitaminosis D was common and not reliably corrected by 400 IU of vitamin D daily. Despite an extremely high osteoporotic fracture risk in NH residents, additional study is required to determine under which conditions pharmacological treatment is efficacious in this population and define approaches that assure vitamin D repletion.     

Early changes in serum N-telopeptide and C-telopeptide cross-linked collagen type 1 predict long-term response to alendronate therapy in elderly women

The aim of this study was to determine whether early changes in serum markers of bone resorption could predict long-term responses in bone mineral density (BMD) after alendronate therapy in elderly women. One hundred and twenty women (mean age, 70 yr) were randomized to alendronate or placebo in this double blind, placebo-controlled clinical trial for 2.5 yr. Outcome measures were hip and spine BMD and biochemical markers of bone resorption, including serum N-telopeptide and C-telopeptide cross-linked collagen type I (NTx and CTx, respectively). Serum NTx and CTx were highly correlated at baseline (r = 0.73; P < 0.001) and remained so throughout the study (range, r = 0.36-0.56; all P < 0.05). After treatment with alendronate, serum NTx decreased 30.4+/-16.0% at 6 months, reaching a nadir of -36.7+/-18.0% by 24 months (P < 0.001). Serum CTx decreased 43.5+/-67.0% at 6 months and continued to decrease to 67.3+/-19.3% at 2.5 yr (P < 0.001). Moreover, decreases in serum NTx and CTx at 6 months were correlated with long-term improvements in vertebral BMD at 2.5 yr in patients receiving alendronate therapy (NTx: r = -0.42; CTx: r = -0.31; both P < 0.05). We conclude that early changes in serum NTx and CTx, markers of bone resorption, predict long-term changes in vertebral BMD in elderly women receiving alendronate therapy and provide a useful tool to assess skeletal health.     

Relationship between biochemical markers of bone turnover and bone scintigraphic indices in assessment of Paget's disease activity

Objective. To evaluate the relationship between biochemical markers of bone turnover and bone scan indices of disease activity, as well as to analyze their variations based on skeletal involvement, in Paget's disease. Methods. Serum samples were obtained from 51 patients with Paget's disease to determine the levels of total alkaline phosphatase (total AP), bone alkaline phosphatase (bone AP), propeptide carboxyterminal of type I procollagen (PICP), propeptide aminoterminal of type I procollagen (PINP), osteocalcin, tartrate-resistant acid phosphatase, and telopeptide carboxyterminal of type I collagen. Urine samples were analyzed for levels of hydroxyproline (HYP), pyridinoline (PYR), deoxypyridinoline (DPYR), C-terminal telopeptide of type I collagen (CTx), and N-terminal telopeptide of type I collagen (NTx). In addition, 2 semiquantitative scintigraphic indices, disease activity (AI) and disease extent (EI), were obtained. Pagetic skeletal locations were evaluated individually, with special attention to skull involvement. Results. All biochemical markers correlated with the AI and the EI. Serum PINP, bone AP, and total AP showed the highest proportions of increased values among the bone formation markers (94%, 82%, and 76%, respectively). Among the bone resorption markers, urinary NTx showed the highest proportion of increased values in patients with Paget's disease (96%), compared with PYR (69%), DPYR (71%), CTx (65%), and HYP (64%). In patients with mild disease activity, serum PINP was the marker with the highest proportion of increased values (71%). In contrast, serum PICP and urinary CTx were the most discriminative markers for skull involvement. Except for higher values for most of the biochemical markers of bone turnover in flat bones, no major differences in other skeletal locations were observed. Conclusion. The determination of serum PINP as a marker of bone formation and urinary NTx as a marker of bone resorption provided the best biochemical profile to ascertain the extent and activity of Paget's disease. In patients with skull involvement, serum PICP and urinary CTx were shown to be the most discriminative markers.     

Osteoclastic function is accelerated in male patients with type 2 diabetes mellitus: the preventive role of osteoclastogenesis inhibitory factor/osteoprotegerin (OCIF/OPG) on the decrease of bone mineral density

To clarify the pathogenesis of altered bone metabolism in diabetic state and its underlying mechanisms, the bone mineral content and fasting levels of serum intact parathyroid hormone (i-PTH), intact osteocalcin (i-OC), tartrate-resistant acid phosphatase (TRAP) and osteoclastgenesis inhibitory factor/osteoprotegerin (OCIF/OPG) were measured in male type 2 diabetic patients and their age-matched controls. In addition, urine levels of osteoclastic markers, C-telopeptide of type I collagen (CTx), deoxypyridinoline (DPD), and N-telopeptide of type I collagen (NTx) were simultaneously determined. Serum levels of i-PTH and i-OC in diabetic patients were significantly lower than those in the controls. Conversely, serum concentrations of TRAP were significantly elevated in diabetic patients. However, no clear correlation was observed between serum i-OC and TRAP. It was also observed that urinary excretion of CTx, DPD, and NTx was significantly increased in the diabetics as compared with the controls. Unexpectedly, serum levels of OCIF/OPG tended to be higher in the diabetic group, and these values exhibited a significantly positive correlation with those of serum TRAP. There was found a significantly negative correlation between serum TRAP and bone mineral density (BMD) and also between serum OCIF/OPG and bone mineral density. It seems probable that OCIF/OPG has a suppressive role on the increased bone resorption to prevent further loss of the skeletal bone mass in type 2 diabetic patients.     

Effects of raloxifene on bone mineral metabolism in postmenopausal Japanese women on hemodialysis

In addition to renal osteodystrophy, postmenopausal women on hemodialysis are at high risk for osteoporosis. Recent studies reported the effects of raloxifene, a selective estrogen receptor modulator for osteoporosis, in postmenopausal women. The present study evaluated the efficacy of raloxifene and its effects on bone mineral metabolism in postmenopausal Japanese patients on dialysis. In a prospective, multicentre study, 17 postmenopausal women on chronic hemodialysis with severe osteoporosis (bone mineral density [BMD]≤2 SD by bone densitometry) were treated with 60 mg/day raloxifene hydrochloride for 12 months. The study also included 10 age-matched control women. Vitamin D and calcium salts were not changed during the study. Intact parathyroid hormone (iPTH), serum calcium and phosphorus, and bone resorption marker (NTx) were measured, and BMD were determined by DEXA, at 0, 6, and 12 months after administration of raloxifene. The mean lumbar spine BMD at baseline was similar in the two groups. Raloxifene therapy (for 12 months) improved lumbar spine BMD (by 2.6%) in 53% of the patients, while 70% of the control group showed a reduction in BMD (by 4.0%). Raloxifene significantly decreased serum calcium and increased iPTH. Our results suggested that raloxifene improved trabecular BMD in postmenopausal Japanese women on hemodialysis. The effects of raloxifene on serum calcium and serum iPTH level suggest it improves bone resorption. Vitamin D and/or calcium salts should be added to raloxifene treatment to avoid secondary hyperparathyroidism.     

The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis

OBJECTIVE: The aim of this study was to compare bone mineral density (BMD) and biochemical markers of bone turnover in patients receiving long-term alendronate therapy who continued alendronate, were switched to raloxifene, or discontinued antiresorptive therapy. DESIGN, PATIENTS, AND INTERVENTIONS: Ninety-nine ambulatory women who were diagnosed with postmenopausal osteoporosis and treated with alendronate (10 mg/d) for a mean period of 43 months were randomized to double-blind raloxifene (60 mg/d; n = 33), placebo (n = 33), or continuation of open-label alendronate (n = 33) for 12 months. Patients continued their assigned treatment in a subsequent 12-month, open-label extension phase. All patients received supplemental calcium (500 mg/d) and vitamin D (800 IU/d). MAIN OUTCOME MEASURES: BMD (lumbar spine, total femur, femoral neck, distal forearm, and total body) and biochemical markers (serum intact amino-terminal propeptide of type I procollagen, type 1 collagen cross-linked C-telopeptide, and osteocalcin) were measured at baseline and follow-up visits. RESULTS: Discontinuation of alendronate therapy resulted in a decrease in lumbar spine BMD at 12 months (-2.66%; P < 0.05), but did not change total femur BMD (+0.35%; nonsignificant). Raloxifene and alendronate, compared with discontinuation, prevented lumbar spine BMD loss (-0.75% and -0.54% at 12 months, respectively; P < 0.05). Raloxifene and alendronate caused a similar increase in total femur BMD at 12 months (1.45% and 1.56%; both P < 0.05 vs. baseline; nonsignificant vs. discontinuation). Patients, who discontinued alendronate therapy experienced an increase in bone turnover. Bone turnover increases were less pronounced in patients taking raloxifene and were absent in those who continued alendronate. Of the three groups, mean bone turnover in raloxifene patients was the closest to premenopausal mean values. CONCLUSIONS: BMD preservation and increase were most pronounced in patients continuing alendronate. Raloxifene treatment, compared with placebo, demonstrated beneficial effects on BMD and bone turnover after discontinuation of long-term alendronate therapy.     

Pegvisomant-induced serum insulin-like growth factor-I normalization in patients with acromegaly returns elevated markers of bone turnover to normal

Active acromegaly is associated with increased biochemical markers of bone turnover. Pegvisomant is a GH receptor antagonist that normalizes serum IGF-I in 97% of patients with active acromegaly. We evaluated the effects of pegvisomant-induced serum IGF-I normalization on biochemical markers of bone and soft tissue turnover, as well as levels of PTH and vitamin D metabolites, in 16 patients (nine males; median age, 52 yr; range, 28-78 yr) with active acromegaly (serum IGF-I at least 30% above upper limit of an age-related reference range). Serum procollagen III amino-terminal propeptide (PIIINP) and type I procollagen amino-terminal propeptide, osteocalcin (OC), bone-related alkaline phosphatase, C-terminal cross-linked telopeptide of type I collagen (CTx), albumin-corrected calcium, intact PTH, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D [1,25-(OH)(2) vit D], urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio, and urinary calcium (24 h collection) were measured (single-batch analysis) at study entry and after IGF-I normalization, along with sera from 32 age- and sex-matched controls. Compared with controls, PIIINP, OC, and CTx were significantly elevated in patients at baseline. Pegvisomant-induced serum IGF-I normalization (699 +/- 76 to 242 +/- 28 micro g/liter, P < 0.001) was associated with a significant decrease in PIIINP, markers of bone formation (type I procollagen amino-terminal propeptide, OC, and bone-related alkaline phosphatase), and resorption (CTx and urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio). 1,25-(OH)(2) vit D decreased and intact PTH increased significantly, but 25-hydroxy vitamin D was unaffected. A significant decline in calculated calcium clearance was observed. The decrease in serum IGF-I correlated positively with the decrease of serum PIIINP (r = 0.7, P < 0.01). After normalization of serum IGF-I, there was no statistical difference between patients and controls for any parameters for which control data were available. In conclusion, GH excess is associated with increased bone and soft tissue turnover. Pegvisomant-induced normalization of serum IGF-I results in a decrease in markers of bone and soft tissue turnover to levels observed in age-matched controls, and these changes are accompanied by an increase in PTH and a decrease in 1,25-(OH)(2) vit D. These data provide further evidence of the effectiveness of pegvisomant in normalizing the altered biological effects of GH hypersecretion.     

Association between baseline values of bone turnover markers and bone mineral density and their response to raloxifene treatment in Japanese postmenopausal women with osteoporosis

It has been well established that raloxifene improves bone turnover, increases bone mineral density (BMD), and reduces the risk of fractures. However, it remains obscure which patients are more likely to respond to treatment with raloxifene in patients with postmenopausal osteoporosis. The purpose of this study was to investigate associations between baseline values of BMD and bone turnover markers (BTMs) and changes of those values after 1-year treatment with raloxifene. Sixty-eight Japanese postmenopausal women with untreated osteoporosis were selected for this study, among whom 58 patients (mean age 70.40 +/- 9.2 years) completed this study. Lower baseline values of BMD at the lumbar spine, the femoral neck, and the distal radius were significantly correlated with greater increases of BMD at those corresponding sites after 1-year treatment with raloxifene. On the other hand, higher baseline values of bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx) were significantly correlated with greater reductions of BAP and NTx, respectively, after 1-year treatment with raloxifene. Although longer and larger studies with fracture endpoints are needed, our findings suggest that baseline values of BMD and BTMs can be used to predict subsequent skeletal response to raloxifene therapy in Japanese postmenopausal women with osteoporosis.     

No difference between strontium ranelate (SR) and calcium/vitamin D on bone turnover markers in women with established osteoporosis previously treated with teriparatide: a randomized controlled trial

Objective   To evaluate the effect of strontium ranelate (SR) on bone turnover markers in women with established osteoporosis previously treated with teriparatide (TPTD – recombinant human PTH 1–34).
Design   patients: Twenty-two postmenopausal Caucasian women (aged 65·7 ± 1·7 years) with established osteoporosis previously treated with TPTD 20 µg daily for 18 months were randomly assigned to receive either SR (SR group, n  = 11) or calcium and vitamin D (control group, n  = 11).
Measurements   Blood samples for serum N-terminal propeptide of type 1 collagen (P1NP), C-terminal telopeptide of type 1 collagen (CTx) and total alkaline phosphatase (ALP) were obtained from all women before (pre-TPTD) and after (post-TPTD) TPTD administration, as well as 6 months after SR or calcium/vitamin D administration (post-SR/Ca).
Results   Serum P1NP, CTx and total ALP increased significantly after TPTD treatment and decreased at the end of the study in both SR and control groups, with no difference between them.
Conclusions   SR following TPTD administration acts predominantly as an antiresorptive agent with no evidence of additional osteoanabolic action. In this setting, SR is not more effective than Ca/vitamin D as far as bone turnover markers are concerned.     

Short-term effects of surgery in post-menopausal patients with primary hyperparathyroidism and normal bone turnover.

The most common clinical presentation of primary hyperparathyroidism (PHPT) is nowadays characterized by a slight skeletal involvement. We studied 5 consecutive female patients with PHPT presenting with bone turnover marker levels within the reference range of our Center and whose bone mineral density values were above the usual fracture risk threshold. In each patient we measured, both in basal conditions and daily, for the first 5 days after surgery, the following indexes: serum total (T-ALP) and bone-specific (B-ALP) alkaline phosphatase activity, osteocalcin (BGP, by two different assays), together with the 24-hour urinary excretions of total pyridinoline (Pyr/Cr) and deoxypyridinoline (DPyr/Cr), free deoxypyridinoline (FD-Pyr/Cr), cross-linked N-telopeptide of type I collagen (NTx/Cr), and type I C-telopeptide (CTx/Cr). The markers of both bone formation and resorption significantly decreased after surgery (p<0.001 by multiple ANOVA). Individual post-surgical markers changes were all significant but T-ALP and FD-Pyr, the most pronounced percent reductions being shown by NTx and CTx. The time-course of such variations substantially differed among the various indexes. These results show that bone formation and resorption markers are up-regulated also in PHPT patients with mild skeletal involvement; acute removal of parathyroid hormone excess differently affected the markers of bone turnover in terms of both entity and time-course.     

Calcium supplement and bone metabolism

Calcium supplementation ameliorates the elevated bone metabolism, especially for the elderly osteoporotic patients, because, calcium suppresses PTH level through the increase of serum calcium level. Urinary deoxypyridinolin, and/or NTx can detect the metabolic changes induced by calcium supplementation. Serum markers such as serum CTx or NTx will detect the small changes more clearly in near future.     

Effect of micronized progesterone on bone turnover in postmenopausal women on estrogen replacement therapy

PURPOSE: To determine whether daily oral micronized progesterone affects bone turnover, as estimated by serum and urine biochemical markers, in postmenopausal women on long-term estrogen replacement therapy (ERT). METHODS: We recruited 14 women aged 65 or older to participate in a 9-week trial with micronized progesterone. Each woman had undergone a hysterectomy and was on unopposed ERT at time of study entry. Women received micronized progesterone 100 mg twice daily in the first week and then received 200 mg twice daily in weeks 2-9. We measured markers of bone turnover in serum and urine collected at baseline and at 3 weeks, 6 weeks, and 9 weeks on treatment. Markers of bone formation were serum bone alkaline phosphatase (BAP), N-terminal procollagen peptides (PINP), and osteocalcin (OC). Markers of bone resorption were urinary cross-linked N-terminal and C-terminal telopeptides of type I collagen. In addition, we measured serum progesterone, estradiol and sex hormone binding globulin, triglycerides, total cholesterol, and high-density lipoprotein (HDL)-cholesterol levels at baseline and at 9 weeks on treatment. RESULTS: Mean serum progesterone levels increased from 1.6 +/- 1.1 to 15.2 +/- 3.9 ng/mL, which was within the luteal phase range (3-25 ng/mL). Crosslinked C-telopeptides of type I collagen and osteocalcin increased significantly (p < 0.05) with progesterone treatment, however, other bone markers did not change. Estradiol, estrone, and SHBG levels did not change with treatment. High-density lipoprotein-cholesterol levels decreased 19% (p < 0.001) at 9 weeks on treatment compared to baseline but total and low-density lipoprotein (LDL) cholesterol and triglycerides did not change with treatment. CONCLUSION: In postmenopausal women on long-term estrogen replacement therapy, micronized progesterone (400 mg/d) increased one marker each of bone resorption and bone formation. Other sensitive markers of bone turnover did not change with treatment. Further, micronized progesterone decreased HDL-cholesterol in these women. Our data do not support a beneficial effect of micronized progesterone on bone or cardiovascular risk factors in postmenopausal women.     

Early changes in biochemical markers of bone turnover are associated with long-term changes in bone mineral density in elderly women on alendronate, hormone replacement therapy, or combination therapy: a three-year, double-blind, placebo-controlled, randomized clinical trial

Elderly women on combination therapy with alendronate and hormone replacement for osteoporosis have greater gains in bone mass than those on monotherapy. It is not known whether early changes in markers can predict the long-term changes in bone density with therapy. We assessed bone density and biochemical markers of bone turnover [urine N-telopeptide cross-linked collagen type 1 (NTx), serum bone-specific alkaline phosphatase, and osteocalcin] every 6 months for 3 yr in a double-blind, placebo-controlled, randomized clinical trial. After a 3-month run-in phase, 373 community-dwelling, elderly women were randomized to 1) alendronate, 2) hormone replacement therapy, 3) combination therapy with alendronate and hormone replacement therapy, or 4) placebo. Women on active treatment with the greatest decrease in markers of bone turnover at 6 months had the greatest increases in spine and hip bone density at 3 yr. The response to alendronate was generally associated with greater reductions in markers than the response to hormone replacement and was associated with greater increases in bone density at the spine and hip. Those in the tertile with the greatest decrease in urinary NTx had a 10.1% increase in spine bone density and a 6.1% increase in hip bone density compared with those in the lowest tertile, who had a 5.9% increase in spine bone density and a 2.1% increase in hip bone density. In women on active treatment, the area under the receiver operator curve for a 6-month change in markers to predict a response in bone mineral density at 3 yr was highest for urine NTx (range, 75-78%) and lowest for osteocalcin (range, 60-66%). We conclude that short-term changes in biochemical markers of bone turnover at 6 months predict bone density changes at the spine and hip at 3 yr in elderly women on alendronate, hormone replacement therapy, or combination therapy.     

A comparison of the effects of raloxifene and conjugated equine estrogen on bone and lipids in healthy postmenopausal women

BACKGROUND: Although many studies have assessed the effects of estrogen and raloxifene hydrochloride on bone mineral density and serum lipid concentrations, there are few direct comparative data. METHODS: Randomized placebo-controlled trial for 3 years, intention-to-treat analysis. Six hundred nineteen postmenopausal women with prior hysterectomy (mean age, 53.0 years) were studied in 38 centers in Europe, North America, Australasia, and South Africa. They were randomized to 60 mg/d or 150 mg/d of raloxifene, 0.625 mg/d of conjugated equine estrogen (CEE), or placebo. Bone density of the lumbar spine and proximal femur, biochemical markers of bone turnover, and fasting serum lipid concentrations were assessed for 3 years. RESULTS: Compared with baseline, bone density in the lumbar spine progressively declined by 2.0% in the placebo group (P <.05), was stable in the 2 raloxifene groups, and increased 4.6% in the subjects receiving CEE (P <.001). Effects in both raloxifene groups were different from those observed in the CEE and placebo groups (P <.001). Bone density in the total hip showed similar results. Conjugated equine estrogen produced significantly greater depression of serum osteocalcin, bone-specific alkaline phosphatase, and urine C-telopeptide, compared with raloxifene. Each of the active treatments caused comparable depression of low-density lipoprotein cholesterol below placebo levels (P <.001 at most time points). Raloxifene did not affect high-density lipoprotein cholesterol, whereas CEE increased it by 13.4% compared with placebo at 3 years (P <.001). Triglyceride concentrations increased 24.6% in the CEE group at 3 years (P <.003), a significantly greater change than in the raloxifene groups, which were 4.9% and 8.0% above baseline (P < or =.002) but not different from placebo. Urinary incontinence was reported in 11 women receiving CEE, but in only 1 or 2 in each of the other groups (P < or =.01 compared with the other groups). Hernias occurred less frequently in those receiving 150 mg/d of raloxifene or CEE (P =.03 vs placebo). CONCLUSIONS: Raloxifene and CEE have beneficial effects on bone density and bone turnover, although effects of CEE are more marked. Raloxifene and CEE produce different patterns of lipid responses and have distinct adverse effect profiles.     

Evidence for increased bone resorption in patients with progressive knee osteoarthritis: longitudinal results from the Chingford study

OBJECTIVE: Several studies have suggested that increased subchondral bone turnover is a determinant of progression of osteoarthritis (OA). To test this hypothesis, the level of urinary N-terminal type I collagen telopeptides (NTx) and C-terminal type I collagen telopeptides (CTx), which are validated markers of bone resorption, was measured at 3 different time points in a subset of patients from the Chingford study. METHODS: The original Chingford study population comprised 1,003 women. From this group, postmenopausal women not receiving any bone-modifying medication who had a baseline knee radiograph and a repeat radiograph 4 years later, and for whom a baseline lumbar spine bone mineral density (BMD) measurement was available, were identified and separated into 4 groups as follows: controls (n = 50), progressive OA (n = 71), nonprogressive OA (n = 36), and osteoporosis (n = 59). NTx and CTx were measured in urine samples collected at baseline, year 1, and year 2. RESULTS: Patient age and years since menopause were similar among groups at baseline. As expected, both body mass index (BMI) and BMD were lowest in patients with osteoporosis. Median resorption marker levels over the 3 time points were 31-87% higher in patients with either progressive OA or osteoporosis than in controls and patients with nonprogressive OA (P < 0.01, except for levels of CTx in patients with progressive OA versus nonprogressive OA). Levels of NTx and CTx did not differ significantly between women with progressive OA (defined either by the presence of osteophytes or by joint space narrowing) and those with osteoporosis or between controls and women with nonprogressive OA. Results were essentially unchanged after adjustment for age, BMI, BMD, and past use of hormone replacement therapy, or when NTx and CTx values at each time point were analyzed separately. CONCLUSION: Our data demonstrate that bone resorption is increased in patients with progressive knee OA and is not increased in those with nonprogressive knee OA. The increase in bone resorption seen in patients with progressive knee OA is similar to that observed in patients with osteoporosis. Altered bone turnover may be a diagnostic or therapeutic target in patients with progressive OA.     

New biochemical markers of bone turnover in serum

Measurement of serum NTx and serum CTx has been recently reported to be a sensitive for osteoporosis and metabolic bone disease. It indicates that the measurement of serum NTx and serum CTx, biochemical markers of bone resorption, predict long-term changes in vertebral BMD in elderly women receiving biophosphonate therapy and provide a useful tool to assess skeletal health.     

骨质疏松患者部分骨代谢指标测定的临床意义

目的 研究血清Ⅰ型胶原氨基末端肽(NTx)和Ⅰ型胶原羧基末端肽(CTx)等指标的检测对于中老年骨质疏松患者的意义. 方法 对165例中老年患者行双能X线骨密度检查,同时检测其血清NTx、CTx、骨型碱性磷酸酶(BAP)、Ⅰ型前胶原氨基末端肽(PINP)、骨钙素(BGP)、白细胞介素6(IL-6)及肿瘤坏死因子α(TNFα),100例体检人员作为对照. 结果 骨质疏松患者BGP和IL-6明显高于对照组(P＜0.05)而TNF-α则与对照组无显著差异.骨质疏松组血清BAP和PINP显著低于对照组和骨量减少组(P＜0.05),NTx及CTx则显著高于对照组和骨量减少组(P＜0.05);而骨量减少组NTx、CTx明也显高于对照组(P＜0.05). 结论 血清NTx和CTx可作为骨吸收的特异性指标,对骨质疏松患者的诊断和疗效评估均具有重要意义.     

Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women: three-year data from 2 double-blind, randomized, placebo-controlled trials

BACKGROUND: In postmenopausal women, raloxifene hydrochloride has favorable effects on bone and lipid metabolism and does not stimulate reproductive tissues. The studies reported herein evaluated the long-term (3-year) effects of raloxifene treatment on bone mineral density (BMD), serum lipid levels, and drug tolerability in healthy postmenopausal women. METHODS: A total of 1145 healthy European and North American postmenopausal women aged 45 through 60 years were enrolled in 2 parallel, double-blind, randomized, placebo-controlled trials of identical design and randomly assigned to receive raloxifene hydrochloride, 30, 60, or 150 mg, or placebo daily; all groups received 400 to 600 mg of elemental calcium. Assessments included measurements for BMD by dual-energy x-ray absorptiometry, markers of bone turnover, and serum lipid levels. RESULTS: Lumbar spine BMD changed from baseline to 36 months as follows: placebo (mean percentage change + SE), -1. 32% +0.22%; raloxifene, 30 mg, 0.71% +0.23%; raloxifene, 60 mg, 1. 28% +0.23%; and raloxifene, 150 mg, 1.20% +0.24%. Comparable BMD changes were observed in the hip and total body. Biochemical markers of bone turnover were suppressed by raloxifene to normal premenopausal ranges through 3 years. Serum low-density lipoprotein cholesterol was reduced 7% to 12% below baseline through 3 years. Study withdrawals due to any reason (37%) and withdrawals due to adverse events (14%) were not different among groups. The only significant adverse effect of therapy was hot flashes (25% in the 60-mg raloxifene group vs 18% in the placebo group); hot flashes were typically reported as mild and were not associated with study withdrawal (1.7% for 60-mg raloxifene vs 2.4% for placebo). CONCLUSIONS: Raloxifene preserves BMD at important skeletal sites, lowers serum low-density lipoprotein cholesterol levels, and has a tolerability profile comparable to placebo. These results indicate a favorable benefit-risk profile of raloxifene for long-term use in healthy postmenopausal women. Arch Intern Med. 2000;160:3444-3450.     

Effects of raloxifene therapy on circulating osteoprotegerin and RANK ligand levels in post-menopausal osteoporosis

Previous in vitro studies suggest that the anti-resorptive effect of raloxifene might be mediated by changes in several cytokines involved in the bone remodeling process. In this context, the osteoprotegerin (OPG)- receptor activator of NF kappa B ligand (RANKL) system is considered a key component in the osteoclastogenesis regulation. The aim of this study was to determine the effects of raloxifene treatment on serum concentrations of OPG, receptor RANKL and its relationship with biochemical markers of bone turnover and bone mineral density (BMD) in previously untreated women with post-menopausal osteoporosis. We selected 47 post-menopausal women (mean age 63+/-7 yr) with densitometric criteria of osteoporosis. We determined at baseline, 3, 6, and 12 months anthropometric parameters, biochemical markers of bone turnover, serum levels of 25(OH) D, serum levels of OPG and RANKL. BMD (dual-energy x-ray absorptiometry) in lumbar spine (LS) femoral neck and total hip was measured at baseline and 12 months after raloxifene (60 mg/day) treatment. Serum levels of OPG decreased in the 3rd and 6th month of treatment (p<0.001) and returned to basal levels in the 12th month. There was a significant decrease of RANKL levels and OPG/RANKL ratio after 1 yr of raloxifene treatment. In addition, BMD in LS increased significantly (2.5%) in the 12th month of treatment (p=0.031). Finally, the biochemical markers of bone turnover (total alkaline phosphatase, bone alkaline phosphatase, osteocalcin, tartrate-resistant acid phosphatase, urine cross-linked carboxi-terminal telopeptide of type I collagen) decreased significantly from the 3rd month of treatment. In conclusion, our results support the hypothesis that raloxifene may inhibit osteoclast activity, at least partly modulating the OPG-RANKL system.