Vitamin K supplementation does not affect ovariectomy-induced bone loss in rats

Vitamin K may be important in bone metabolism. Notably, high-dose menaquinone-4 (menatetrenone, MK4) has been reported to reduce ovariectomy (ovx)-induced bone loss in rats and to decrease osteoporotic fracture in postmenopausal women. However, it is unclear whether these beneficial effects reflect a physiologic effect of vitamin K, or indicate direct pharmacologic activity of MK4. To further evaluate this, 60 6-month-old nulliparous Sprague-Dawley rats were randomized by distal femur bone mineral density (BMD) in a 3:1 ratio to ovx or sham groups. The sham and one ovx group’s diet contained 1% calcium and 1300 μg/kg of vitamin K1, phylloquinone. Diets of the other two ovx groups were supplemented with 882 mg phylloquinone or MK4 per kilogram chow. Distal femur bone mineral density (DFBMD) in an 8 mm region of interest was measured at baseline, 1 and 3 months postoperatively, utilizing dual-energy X-ray absorptiometry (DXA). All animals were killed at 3 months, their right femurs excised, ex vivo BMD measured by DXA, and biomechanical testing performed. No effect of phylloquinone or MK4 supplementation on ovx-induced bone loss was observed. Specifically, DFBMD declined 10.5%, 9.2%, and 11.2% at 1 month and 14.4%, 10.6%, and 13.9% at 3 months in the ovx control, high phylloquinone, and high MK4 groups, respectively. In addition, serum osteocalcin was elevated by ovx; this was not altered by phylloquinone or MK4. Finally, femoral biomechanical properties were not affected by phylloquinone or MK4. To conclude, in this study, neither high-dose phylloquinone nor MK4 reduced the ovx-associated increase in bone turnover or decline in DFBMD.     

Odanacatib,a cathepsin‐K inhibitor for osteoporosis: A two‐year study in postmenopausal women with low bone density

Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. A 1‐year dose‐finding trial with a 1‐year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD) to evaluate the safety and efficacy of weekly doses of placebo or 3, 10, 25, or 50 mg of odanacatib on BMD and biomarkers of skeletal remodeling. Women with BMD T‐scores of ?2.0 or less but not less than ?3.5 at the lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib; all received vitamin D with calcium supplementation as needed. The primary endpoint was percentage change from baseline lumbar spine BMD. Other endpoints included percentage change in BMD at hip and forearm sites, as well as changes in biomarkers of skeletal remodeling. Twenty‐four months of treatment produced progressive dose‐related increases in BMD. With the 50‐mg dose of odanacatib, lumbar spine and total‐hip BMD increased 5.5% and 3.2%, respectively, whereas BMD at these sites was essentially unchanged with placebo (?0.2% and ?0.9%). Biochemical markers of bone turnover exhibited dose‐related changes. The safety and tolerability of odanacatib generally were similar to those of placebo, with no dose‐related trends in any adverse experiences. In summary, 2 years of weekly odanacatib treatment was generally well‐tolerated and increased lumbar spine and total‐hip BMD in a dose‐related manner in postmenopausal women with low BMD. © 2010 American Society for Bone and Mineral Research     

Risedronate improves proximal femur bone density and geometry in patients with osteoporosis or osteopenia and clinical risk factors of fractures: a practice-based observational study

The purpose of this practice-based observational study was to clarify the acute effect of risedronate on proximal femur bone mineral density (BMD) and structural geometry in patients with an increased risk of fractures. One hundred sixty-four patients (7 men and 157 postmenopausal women; mean age, 69.2 years) with osteoporosis or osteopenia and clinical risk factors of fractures were analyzed. All these patients were treated with risedronate for 1 year. Urinary levels of cross-linked N-terminal telopeptide of type I collagen (NTX) were measured at baseline and 4 months after the start of treatment. BMD of the lumbar spine and proximal femur and structural geometric parameters of the proximal femur were evaluated by dual-energy X-ray absorptiometry with advanced hip assessment (AHA) software at baseline and every 4 months. Urinary NTX levels significantly decreased after 4 months of treatment. BMD of the femoral neck and total hip significantly increased after 4, 8, and 12 months of treatment. Cross-sectional moment of inertia (CSMI) and cross-sectional area significantly increased after 4, 8, and 12 months of treatment. An increase in CSMI was apparently greater than those of proximal femur BMD after 4 months of treatment. These results suggest the acute (4 months) and sustained (12 months) effect of risedronate on proximal femur structural geometry as well as BMD as a result of suppression of bone resorption in patients with an increased risk of fractures.     

The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis

This study evaluated the efficacy and tolerability of risedronate once a week (35 mg and 50 mg) compared with risedronate 5 mg once daily in women with osteoporosis. We conducted a randomized, double-blind, active-controlled, 2-year study; the primary efficacy assessment was performed after 1 year. Subjects were women aged 50 years or older who had been postmenopausal for at least 5 years, with either a bone mineral density (BMD) T-score of -2.5 or lower (lumbar spine or proximal femur) or a T-score lower than -2 and at least one prevalent vertebral fracture. Subjects received risedronate 5 mg once daily, 35 mg once a week or 50 mg once a week. All subjects also received 1 g daily of elemental calcium supplementation and supplemental vitamin D if the baseline serum levels were low. The primary efficacy measure was percent change in lumbar spine BMD at 12 months. A total of 1,456 women were randomized and received medication; 1,209 (83%) women completed 12 months. The mean percent change (SE) in lumbar spine BMD after 12 months was 4.0% (0.2%) in the 5 mg daily group, 3.9% (0.2%) in the 35 mg group, and 4.2% (0.2%) in the 50 mg group; each once-a-week treatment was determined to be as effective as the daily treatment. Outcomes of the secondary efficacy measurements and safety assessments were also similar in all 3 groups after 12 months. Risedronate 35 mg and 50 mg once a week provide the same efficacy and safety as the daily 5 mg regimen; therefore, the lower dose, 35 mg once a week, is considered optimal for women with postmenopausal osteoporosis who desire a once-a-week regimen.     

Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.

Dietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius. INTRODUCTION: The putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age. MATERIALS AND METHODS: Healthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables. RESULTS: Significant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049). CONCLUSIONS: These results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.     

Effects of Bazedoxifene on BMD and Bone Turnover in Postmenopausal Women: 2‐Yr Results of a Randomized,Double‐Blind,Placebo‐, and Active‐Controlled Study

Osteoporosis is an increasingly common health concern in postmenopausal women. In a 2‐yr phase III study, bazedoxifene prevented bone loss, reduced bone turnover, and was well tolerated in early postmenopausal women with normal or low BMD. Introduction : Bazedoxifene is a novel selective estrogen receptor modulator that has increased BMD and bone strength in experimental models, without stimulating breast or uterus. This 24‐mo, randomized, double‐blind study assessed the efficacy and safety of three doses of bazedoxifene compared with placebo and raloxifene in the prevention of postmenopausal osteoporosis. Materials and Methods : Healthy postmenopausal women with a BMD T‐score at the lumbar spine or femoral neck between –1.0 and ?2.5 or clinical risk factors for osteoporosis were randomly assigned to one of five groups: bazedoxifene 10, 20, or 40 mg/d, placebo, or raloxifene 60 mg/d. All women received elemental calcium. Efficacy outcomes included changes from baseline through 24 mo in BMD of the lumbar spine, hip, femoral neck, and femoral trochanter and biomarkers of bone metabolism. Results : The intent‐to‐treat population included 1434 women (mean age, 58 yr; mean time from last menstrual period, 11 yr). All doses of bazedoxifene and raloxifene prevented bone loss, whereas in the placebo group, there was significant loss of BMD at all skeletal sites. Mean differences in percent change in lumbar spine BMD from baseline to 24 mo relative to placebo were 1.08 ± 0.28%, 1.41 ± 0.28%, 1.49 ± 0.28%, and 1.49 ± 0.28% for 10, 20, and 40 mg bazedoxifene and 60 mg raloxifene, respectively (p < 0.001 for all comparisons). Comparable BMD responses were observed at other body sites. Significant and comparable decreases in serum osteocalcin and C‐telopeptide levels from baseline and relative to placebo with active treatment were observed as early as 3 mo and were sustained through study conclusion (p < 0.001). Overall incidences of adverse events, serious adverse events, and discontinuations caused by adverse events were similar between groups. The most common adverse events included headache, infection, arthralgia, pain, hot flush, and back pain. Conclusions : Treatment with bazedoxifene prevented bone loss and reduced bone turnover equally as well as raloxifene and was generally well tolerated in postmenopausal women with normal/low BMD.     

Randomized Controlled Trial of the Effects of Calcium With or Without Vitamin D on Bone Structure and Bone‐Related Chemistry in Elderly Women With Vitamin D Insufficiency

There are few data on the relative effects of calcium supplementation with or without extra vitamin D on BMD in patients selected for low vitamin D status. The aim of this study is to evaluate the relative importance of vitamin D and calcium treatment on BMD and bone‐related chemistry in elderly women with vitamin D insufficiency. Three hundred two elderly women (age, 77.2 ± 4.6 yr) with serum 25(OH)D concentrations <60 nM participated in a 1‐yr randomized, double‐blind, placebo‐controlled trial. All subjects received 1000 mg calcium citrate per day with either 1000 IU ergocalciferol (vitamin D₂) or identical placebo (control). The effects of time and time treatment interactions were evaluated by repeated‐measures ANOVA. At baseline, calcium intake was 1100 mg/d, and 25(OH)D was 44.3 ± 12.9 nM; this increased in the vitamin D group by 34% but not the control group after 1 year (59.8 ± 13.8 versus 45.0 ± 13.3 nM, p < 0.001). Total hip and total body BMD increased significantly, and procollagen type I intact N‐terminal propeptide (PINP) decreased during the study with no difference between the treatment groups (hip BMD change: vitamin D, +0.5%; control, +0.2%; total body BMD change: vitamin D, +0.4%; control, +0.4%; PINP change: vitamin D, ?3.9%; placebo, ?2.8%). Although the fasting plasma and urine calcium increased in both groups equally, there was no detectable change in serum PTH. The increase in 25(OH)D achieved with vitamin D supplementation had no extra effect on active fractional intestinal calcium absorption, which fell equally in both groups (vitamin D, ?17.4%; control, ?14.8%). In patients with a baseline calcium intake of 1100 mg/d and vitamin D insufficiency, vitamin D₂ 1000 IU for 1 year has no extra beneficial effect on bone structure, bone formation markers, or intestinal calcium absorption over an additional 1000 mg of calcium. Vitamin D supplementation adds no extra short‐term skeletal benefit to calcium citrate supplementation even in women with vitamin D insufficiency.     

Effects of long-term vitamin K(1) (phylloquinone) or vitamin K(2) (menaquinone-4) supplementation on body composition and serum parameters in rats

Vitamin K is a cofactor for γ-glutamyl carboxylase, which is an essential enzyme for the γ-carboxylation of vitamin K-dependent proteins such as osteocalcin and matrix Gla protein. Although it has been suggested that vitamin K plays an important role in the improvement of bone metabolism, the relationship between dietary vitamin K intake and bone metabolism has not been thoroughly investigated. Moreover, vitamin K is thought to have other actions beyond influencing the γ-carboxylation status. In the present study, we examined the effects of the long-term addition of phylloquinone (PK) or menaquinone-4 (MK-4) to a control diet on bone mineral density, bone strength, body composition, and serum parameters in rats. A total of 23 female Sprague-Dawley strain rats (6 weeks old) were divided into three groups: basic control diet group, PK diet (PK: 600mg/kg diet) group, and MK diet (MK-4: 600mg/kg diet) group. Three months after starting the experimental diet, the addition of PK to the basic control diet significantly increased the bone mineral density (BMD) of the femur (p<0.05). In the MK group, there was no significant difference in the BMD of the femur. However, two types of bone strength parameter: the minimum cross-sectional moment of inertia and the polar moment of inertia, were significantly higher in the MK group than in the control (p<0.05, respectively). Furthermore, the femoral bone parameters (the width, dry weight and ash weight, and cortical, cancellous, trabecular, and total bone mineral contents) in the MK group were increased significantly compared with the control. Interestingly, the addition of PK or MK-4 significantly decreased the total fat accumulation (p<0.01 and p<0.05, respectively), and serum triglycerides were reduced by 48% in the PK group and 29% in the MK group compared with the control. There were no significant differences in the levels of serum calcium, phosphorus, alkaline phosphatase, growth hormone, insulin-like growth hormone-1, insulin-like growth hormone binding protein-3, and cross-linked N-teleopeptide of type I collagen among the three groups. This is the first study to demonstrate the effect of the long-term addition of PK or MK-4 to the control diet on body composition and serum parameters in an in vivo system using rats. Further studies on the mechanism of vitamin K supplementation in the regulation of bone metabolism would provide valuable data on the prevention of lifestyle-related disorders, including osteoporosis.     

Predictive value of a preoperative biochemical bone marker in relation to bone remodeling after cementless total hip arthroplasty.

To identify the factors predicting proximal bone resorption of the femur after cementless total hip arthroplasty (THA), we studied 24 postmenopausal women with osteoarthritis. Periprosthetic bone mineral density (BMD) measurements of the seven Gruen zones were determined with dual-energy X-ray absorptiometry at 3 wk, 6, 12, and 18 mo after operation. The greatest decrease in BMD (13.2%) was found in zone 7 at 18 mo. At 18 mo, preoperative serum bone alkaline phosphatase was associated univariately with BMD loss in zones 1 (r = 0.407, p = 0.048) and 7 (r = 0.543, p = 0.006) and urinary N-telopeptide cross-linked collagen type I (NTX) was associated univariately with that in zone 7 (r = 0.520, p = 0.009). Patient age correlated with BMD loss in zone 7 (r = 0.425, p = 0.039). Multiple regression analysis identified a significant relationship between the BMD loss and patient age and NTX in zone 7 at 18 mo (r2 = 0.422, p = 0.001). We conclude that preoperative bone markers are significant predictors of bone remodeling after THA with the particular implants used in our study.     

The effects of whole‐body vibration training and vitamin D supplementation on muscle strength,muscle mass,and bone density in institutionalized elderly women: A 6‐month randomized,controlled trial

Sarcopenia and osteoporosis represent a growing public health problem. We studied the potential benefit of whole‐body vibration (WBV) training given a conventional or a high dose of daily vitamin D supplementation in improving strength, muscle mass, and bone density in postmenopausal women. In a 2 × 2 factorial‐design trial, 113 institutionalized elderly females aged over 70 years (mean age 79.6 years) were randomly assigned either to a WBV or a no‐training group, receiving either a conventional dose (880 IU/day) or a high dose (1600 IU/day) of vitamin D₃. The primary aim was to determine the effects of 6 months of WBV and/or vitamin D supplementation on isometric and dynamic strength, leg muscle mass, and hip bone mineral density (BMD). Additionally, the increase in 25‐hydroxyvitamin D [25(OH)D] levels between conventional and high‐dose supplementation was compared. After 6 months of treatment, dynamic muscle strength, hip BMD, and vitamin D serum levels improved significantly in all groups, whereas isometric strength and muscle mass did not change. When compared with no training, the WBV program did not result in additional improvements. When compared with 880 IU, a high dose of 1600 IU of vitamin D did result in higher serum vitamin D levels but did not result in additional improvements. In institutionalized women older than 70 years, the WBV training protocol tested is not more efficient in enhancing muscle mass, strength, and hip BMD compared with vitamin D supplementation. A higher dose of 1600 IU of vitamin D does not provide additional musculoskeletal benefit in this population compared with conventional doses. © 2011 American Society for Bone and Mineral Research.     

Effects of cyclical etidronate with alfacalcidol on lumbar bone mineral density,bone resorption,and back pain in postmenopausal women with osteoporosis

The purpose of the present open-labeled, randomized, prospective study was to compare the effects of cyclical etidronate combined with alfacalcidol with those of cyclical etidronate alone on lumbar bone mineral density (BMD), bone resorption, and back pain in postmenopausal women with osteoporosis. Forty postmenopausal women with osteoporosis, 60–86 years of age, without any vertebral fractures in the lumbar spine, were randomly divided into two groups with 20 patients in each group. One group was treated with cyclical etidronate (oral etidronate 200mg daily for 2 weeks every 3 months) and the other was given cyclical etidronate combined with alfacalcidol (cyclical etidronate plus alfacalcidol 1Ìg daily continuously). The BMD of the lumbar spine (L1–L4) measured by dual-energy X-ray absorptiometry, urinary crosslinked N-terminal telopeptides of type I collagen (NTX) measured by an enzyme-linked immunosorbent assay, and back pain evaluated by the face scale score were assessed at baseline, 6 months, and 12 months. There were no significant differences in baseline characteristics including age, body mass index, years since menopause, lumbar BMD, urinary NTX level, and face scale score between the two treatment groups. Both treatments significantly reduced the urinary NTX level and back pain. Cyclical etidronate combined with alfacalcidol significantly increased the lumbar BMD with a more significant reduction in the urinary NTX level than cyclical etidronate alone, but cyclical etidronate alone did not significantly increase the lumbar BMD. Alleviation of back pain was similar in the two groups. These results suggest that cyclical etidronate combined with alfacalcidol appears to be more useful than cyclical etidronate alone for increasing the lumbar BMD by more markedly suppressing bone resorption in postmenopausal women with osteoporosis.     

Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease

A high incidence of fractures, particularly of the hip, represents an important problem in patients with Alzheimer's disease (AD), who are prone to falls and may have osteoporosis. We previously showed deficiency of vitamins D and K1 causes reduced bone mineral density (BMD) in female AD patients. The present study was undertaken to address the possibility that treatment with vitamin K2 (menatetrenone; MK-4) may maintain BMD and reduce the incidence of nonvertebral fractures in elderly female patients with AD. In a random and prospective study of AD patients, 100 patients received 45 mg menatetrenone, 1000 IU ergocalciferol and 600 mg calcium daily for 2 years, and the remaining 100 (untreated group) did not. At baseline, patients of both groups showed vitamin D and K1 deficiencies. They also had high serum levels of parathyroid hormone (PTH) and Glu osteocalcin (OC) and low serum ionized calcium, indicating that vitamin D deficiency stimulates compensatory PTH secretion. During the 2-year study period, BMD in the second metacarpals increased by 2.3% in the treated group and decreased by 5.2% in the untreated group (P < 0.0001). Serum levels of vitamin K2 and 25-hydroxyvitamin D increased by 284.9% and 147.9%, respectively, in the treated group. Correspondingly, a significant decrease in Glu OC and PTH were observed, in association with an increased calcium levels, in the treated group. Twenty-two patients in the untreated group sustained nonvertebral fractures (15 with hip fractures, two fractures each at the distal forearm and the proximal femur, each one fracture at the proximal humerus, ribs, and pelvis), and three fractures (2 with hip fractures, one fracture at the proximal femur) occurred among the treated patients (P = 0.0003; odds ratio = 7.5). Treatment with MK-4 and vitamin D2 with calcium supplements increases the BMD in elderly female patients with AD and leads to the prevention of nonvertebral fractures.     

A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) trial

The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double‐blind, double‐dummy, active‐ and placebo‐controlled, multiple‐dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2 mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (≥1000 mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean ± SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% ± 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% ± 2.9%) or placebo (0.5% ± 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one‐half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis. © 2012 American Society for Bone and Mineral Research.     

Effect of low‐dose calcium supplements on bone loss in perimenopausal and postmenopausal Asian women: A randomized controlled trial

Current standard‐dose calcium supplements (eg, 1000 mg/d) may increase the risk for cardiovascular events. Effectiveness of lower‐dose supplements in preventing bone loss should thus be considered. This study aimed to assess whether calcium supplements of 500 or 250 mg/d effectively prevent bone loss in perimenopausal and postmenopausal Japanese women. We recruited 450 Japanese women between 50 and 75 years of age. They were randomly assigned to receive 500 mg of calcium (as calcium carbonate), 250 mg of calcium, or placebo daily. Medical examinations conducted three times over a 2‐year follow‐up period assessed bone mineral density (BMD) of the lumbar spine and femoral neck. One‐factor repeated measures ANOVA was used for statistical tests. Subgroup analyses were also conducted. Average total daily calcium intake at baseline for the 418 subjects who underwent follow‐up examinations was 493 mg/d. Intention‐to‐treat analysis showed less dramatic decreases in spinal BMD for the 500‐mg/d calcium supplement group compared to the placebo group (1.2% difference over 2 years, p = 0.027). Per‐protocol analysis (≥80% compliance) revealed that spinal BMD for the 500‐mg/d and 250‐mg/d calcium supplement groups decreased less than the placebo group (1.6%, p = 0.010 and 1.0%, p = 0.078, respectively), and that femoral neck BMD for the 500‐mg/d calcium supplement group decreased less relative to the placebo group (1.0%, p = 0.077). A low‐dose calcium supplement of 500 mg/d can effectively slow lumbar spine bone loss in perimenopausal and postmenopausal women with habitually low calcium intake, but its effect on the femoral neck is less certain. Calcium supplementation dosage should thus be reassessed. (Clinical Trials Registry number: UMIN000001176). © 2012 American Society for Bone and Mineral Research.     

Sexual differences in bone markers and bone mineral density of normal Chinese

We measured bone mineral density (BMD) at lumbar (L2–L4) vertebrae and proximal femurs of 385 healthy Chinese women aged 40–70 years and 156 healthy Chinese men aged 20–85, and four markers—bone alkaline phosphatase isozyme (BAP), procollagen-I C terminal propeptide (PICP), osteocalcin (BGP) in serum, and a bone resorption marker, urinary cross-linked N-telopeptide of type I collagen (NTX), of these subjects. The results indicate that in postmenopausal women, levels of all the markers increased with age. In men, serum BAP, PICP, and urinary NTX decreased significantly, and serum BGP decreased with borderline significance (P=0.08). With increasing age, bone density decreased at both sites in post-menopausal women and at the proximal femur in men. The lumbar bone density showed no significant age-related changes in men. In premenopausal women, BMD at either site showed no significant change with increasing age. Despite the different trends between men and women of agerelated changes in BMD and bone markers, bone density of both proximal femur and spine in both sexes correlated inversely with levels of the bone markers in a manner independent of age or body weight. The meaning of opposite age effects on bone markers in men and women needs further investigation. In addition, higher bone marker levels, implying faster bone turnover rate, are associated with lower BMD in both sexes.     

Once‐Weekly Risedronate in Men With Osteoporosis: Results of a 2‐Year,Placebo‐Controlled,Double‐Blind,Multicenter Study

Male osteoporosis is increasingly recognized as a major public health issue. This multinational, 2‐yr, randomized, double‐blind, placebo‐controlled study was conducted to determine the efficacy and safety of 35 mg once‐a‐week risedronate in men with osteoporosis. Patients had to be men ≥30 yr old, with lumbar spine T‐score ≤ ?2.5 and femoral neck T‐score ≤ ?1 SD or lumbar spine T‐score ≤ ?1 and femoral neck T‐score ≤ ?2 SD (based on young normal men). Patients were randomized 2:1 to risedronate 35 mg once a week or placebo for 2 yr; all patients took 1000 mg elemental calcium and 400–500 IU vitamin D daily. Lumbar spine BMD at month 24 using last observation carried forward was the primary endpoint. Other endpoints included lumbar spine BMD at time points other than month 24, proximal femur BMD, bone turnover markers (BTMs), new vertebral fractures, clinical fractures, and adverse event (AE) assessment. There were 284 men enrolled in the study. Treatment with risedronate resulted in a significant increase from baseline to endpoint in lumbar spine BMD compared with placebo (4.5%; 95% CI: 3.5%, 5.6%; p < 0.001). Few new vertebral and nonvertebral fractures were reported, with no differences in fracture rates between the two groups. There was a significant (p < 0.01) reduction from baseline in BTMs for the risedronate group compared with placebo at all time points. No apparent differences in the pattern or distribution of AEs including serious and upper gastrointestinal AEs were observed. Risedronate therapy was well tolerated during this 2‐yr study and was rapidly effective as indicated by significant BTM decreases at month 3 and BMD increases at month 6 (the earliest time points tested). The effects of risedronate treatment on BMD and BTMs in this study were similar to those previously shown to be associated with fracture risk reductions in women with postmenopausal osteoporosis.     

Diet- or warfarin-induced vitamin K insufficiency elevates circulating undercarboxylated osteocalcin without altering skeletal status in growing female rats.

To further characterize the skeletal role of vitamin K (K), markers of bone turnover, density, and strength were evaluated in rats with diet- or warfarin (W)-induced K insufficiency. One hundred two, 7-week-old, female rats were randomly assigned to low K (phylloquinone [K1], 20 microg/kg diet), control K (K1, 1300 microg/kg diet), low-dose W (W, 1.5 mg/kg control diet), or high-dose W plus K (W/K1, 10/100 mg/kg diet). Femur bone mineral content (BMC) and bone mineral density (BMD), plasma prothrombin time (PT) and prothrombin concentration (PC), and serum total alkaline phosphatase (ALP) and skeletal alkaline phosphatase (sALP) were measured at baseline and days 20, 40, 60, and 80. Serum total osteocalcin (OC) and undercarboxylated osteocalcin (ucOC) and femur length (FL) were measured at baseline and day 80. Left femur OC was measured and biomechanical testing of the right femur and third lumbar vertebral body was performed at day 80. Low dietary K elevated circulating ucOC (17% higher than control; p < 0.0001) at day 80. Furthermore, in both W groups, essentially all circulating OC was undercarboxylated and femur OC was lower than control (p < 0.0001). However, there was no change in femur percent ucOC, suggesting deposition of less newly synthesized OC. No between group differences were observed in PT, ALP, sALP, FL, BMC, BMD, or bone strength. In conclusion, skeletal K insufficiency can be induced by W or diet manipulation. This does not hinder peak bone mass attainment in female rats; however, W causes less newly synthesized OC to be deposited in bone.     

维生素D、维生素B12和同型半胱氨酸水平与绝经后女性骨密度的相关性研究

目的探索绝经后非骨质疏松症和骨质疏松症女性患者高半胱氨酸、维生素D、维生素B_(12)和骨密度(bone mineral density,BMD)之间的关系。方法选取2017年8～12月在我院就诊的138名女性作为研究对象,根据骨密度将绝经后女性分为骨质疏松组(n=58)和非骨质疏松组(n=80)。记录两组患者的体质量指数(body mass index,BMI)、年龄、腰围等一般资料,检测腰椎L_(1～4)前后位、左侧股骨近端的BMD,测定血清同型半胱氨酸、维生素B_(12)、维生素D、碱性磷酸酶、钙、磷水平。分析两组患者不同指标的差异以及高半胱氨酸、维生素D、维生素B_(12)和BMD之间的相关性。结果两组患者的年龄、BMI、腰围、同型半胱氨酸、维生素D、维生素B_(12)、腰椎L_(1～4)和左股骨颈骨密度比较差异有统计学意义(P均0.05);Rho相关性和回归分析表明,同型半胱氨酸与维生素D和B_(12)在绝经后非骨质疏松症和同型半胱氨酸与维生素B_(12)在绝经后骨质疏松症女性中呈显著负相关。结论高水平同型半胱氨酸可以通过绝经后非骨质疏松症患者维生素D水平和绝经后骨质疏松症女性维生素B_(12)水平预测。     

Effect of walking exercise on bone metabolism in postmenopausal women with osteopenia/osteoporosis

The purpose of this prospective study was to determine whether moderate walking exercise in postmenopausal women with osteopenia/osteoporosis would affect bone metabolism. Fifty postmenopausal women, aged 49–75 years, with osteopenia/osteoporosis were recruited: 32 women entered the exercise program (the exercise group) and 18 served as controls (the control group). The exercise consisted of daily outdoor walking, the intensity of which was 50% of maximum oxygen consumption, with a duration of at least 1h with more than 8000 steps, at a frequency of 4 days a week, over a 12-month period. Lumbar (L2–L4) bone mineral density (BMD) was measured at the baseline and every 6 months with dual-energy X-ray absorptiometry (DXA) in both groups. Serum bone-specific alkaline phosphatase (BAP) and urinary cross-linked N-terminal telopeptides of type I collagen (NTX) levels were measured at baseline and at months 1, 3, 6, 9, and 12 by EIA and ELISA, respectively, in the exercise group, and urinary NTX level was measured at the baseline and every 6 months in the control group. There were no significant differences in baseline characteristics including age, height, body weight, bone mass index, years since menopause, lumbar BMD, and urinary NTX level between the two groups. Although no significant changes were observed in lumbar BMD and the urinary NTX level in the control group, lumbar BMD in the exercise group was increased as compared with the control group, but was sustained from the baseline. In the exercise group, the urinary NTX level rapidly responded to walking exercise from month 3, and this reduction was sustained until month 12, followed by reduction in the serum BAP level. A moderately negative correlation was found between the percent change in the urinary NTX level at month 3 and that in lumbar BMD at month 12 in the exercise group. This study clearly demonstrates that the mechanism for the positive response of lumbar BMD to moderate walking exercise in postmenopausal women with osteopenia/osteoporosis appears to be the suppression of bone turnover, and that an early change in the urinary NTX level may be useful to predict the long-term response of increasing lumbar BMD to exercise, although its efficacy for lumbar BMD may be quite modest.     

Assessment of age and risk factors on bone density and bone turnover in healthy premenopausal women

The influence of age and risk factors on bone density and bone turnover was evaluated in 249 healthy premenopausal women. Risk factors were assessed by standardized questionnaires and included reproductive history and lifestyle factors (intake of calcium and vitamin D supplements, consumption of caffeine, smoking habits and physical activity). Bone mineral density (BMD) measurements were obtained in the distal forearm, the lumbar spine and the proximal femur. Bone turnover were assessed by plasma bone Gla proteins (pBGP) and fasting urinary hydroxyproline corrected for creatinine (fUHPr/Cr). Peak bone density seems to be achieved before the age of 30 years, whereafter we found no appreciable bone loss at any skeletal site. Accordingly, the levels of pBGP and fUHPr/Cr were increased before the age of 30, whereafter the values stabilized at a lower level. A dairy calcium intake above 660 mg/day significantly increased BMD in the spine and proximal femur by 3%–5%. Physical activity alone had no influence on BMD, but in combination with calcium intake an additive effect was observed. Women who had an active lifestyle (corresponding to at least 1 h of daily walking) and a dairy calcium intake above 660 mg/day had a 3%–7% increase in BMD compared with more sedentary women with a calcium intake below this limit. Vitamin D supplements, caffeine, smoking and reproductive history did not consistently influence BMD or bone turnover. Only pBGP was selectively reduced by smoking and current use of oral contraceptives, respectively. We conclude that there is no appreciable change in BMD before the menopause once skeletal maturity has been reached. Dietary calcium intake increases peak bone density and this positive effect can be potentiated by an active lifestyle. Other putative risk factors had no influence on premenopausal BMD.