A positive dose-response effect of vitamin D supplementation on site-specific bone mineral augmentation in adolescent girls: a double-blinded randomized placebo-controlled 1-year intervention.

The effect of vitamin D supplementation on bone mineral augmentation in 212 adolescent girls with adequate calcium intake was studied in a randomized placebo-controlled setting. Bone mineral augmentation determined by DXA increased with supplementation both in the femur and the lumbar vertebrae in a dose-responsive manner. Supplementation decreased the urinary excretion of resorption markers, but had no impact on formation markers. INTRODUCTION: Adequate vitamin D intake protects the elderly against osteoporosis, but there exists no indisputable evidence that vitamin D supplementation would benefit bone mineral augmentation. The aim of this 1-year study was to determine in a randomized double-blinded trial the effect of 5 and 10 microg vitamin D3 supplementation on bone mineral augmentation in adolescent girls with adequate dietary calcium intake. MATERIALS AND METHODS: Altogether, 228 girls (mean age, 11.4 +/- 0.4 years) participated. Their BMC was measured by DXA from the femur and lumbar spine. Serum 25-hydroxyvitamin D [S-25(OH)D], intact PTH (S-iPTH), osteocalcin (S-OC), and urinary pyridinoline (U-Pyr) and deoxypyridinoline (U-Dpyr) were measured. Statistical analysis was performed both with the intention-to-treat (IT) and compliance-based (CB) method. RESULTS: In the CB analysis, vitamin D supplementation increased femoral BMC augmentation by 14.3% with 5 microg and by 17.2% with 10 microg compared with the placebo group (ANCOVA, p = 0.012). A dose-response effect was observed in the vertebrae (ANCOVA, p = 0.039), although only with the highest dose. The mean concentration of S-25(OH)D increased (p < 0.001) in the 5-microg group by 5.7 +/- 15.7 nM and in the 10-microg group by 12.4 +/- 13.7 nM, whereas it decreased by 6.7 +/- 11.3 nM in the placebo group. Supplementation had no effect on S-iPTH or S-OC, but it decreased U-DPyr (p = 0.042). CONCLUSIONS: Bone mineral augmentation in the femur was 14.3% and 17.2% higher in the groups receiving 5 and 10 microg of vitamin D, respectively, compared with the placebo group, but only 10 mug increased lumbar spine BMC augmentation significantly. Vitamin D supplementation decreased the concentration of bone resorption markers, but had no impact on bone formation markers, thus explaining increased bone mineral augmentation. However, the positive effects were noted with the CB method but not with IT.     

The Effect of Vitamin K and D Supplementation on Ovariectomy-Induced Bone Loss

This study was designed to assess the effect of vitamin K and D supplementation on ovariectomy-induced bone loss. Female Sprague-Dawley rats aged 8–9 months were ovariectomized (OVX) or sham operated and divided into five experimental groups: (1) ovariectomy (OVX), (2) OVX plus vitamin K supplementation, (3) OVX plus vitamin D supplementation, (4) OVX plus vitamin K and vitamin D supplementation, and (5) sham operation. The trabecular bone area was estimated by bone histomorphometry by microradiography and histological examination. Bone loss in OVX plus vitamin K and vitamin D group was significantly reduced at both 7 and 14 weeks compared with the OVX group. No significant bone loss in OVX plus vitamin K or OVX plus vitamin D groups was found. A similar effect of vitamin K and D supplementation on ovariectomy-induced bone loss was recognized in histological examination. Our findings indicate that vitamins K and D may have a synergistic effect on reducing bone loss. This is valuable information for the treatment of bone loss in postmenopausal women with osteoporosis. Received: 1 September 1998 / Accepted: 10 January 1999     

Calcium- and vitamin D3-fortified milk reduces bone loss at clinically relevant skeletal sites in older men: a 2-year randomized controlled trial.

In this 2-year randomized controlled study of 167 men >50 years of age, supplementation with calcium-vitamin D3-fortified milk providing an additional 1000 mg of calcium and 800 IU of vitamin D3 per day was effective for suppressing PTH and stopping or slowing bone loss at several clinically important skeletal sites at risk for fracture. INTRODUCTION: Low dietary calcium and inadequate vitamin D stores have long been implicated in age-related bone loss and osteoporosis. The aim of this study was to assess the effects of calcium and vitamin D3 fortified milk on BMD in community living men >50 years of age. MATERIALS AND METHODS: This was a 2-year randomized controlled study in which 167 men (mean age +/- SD, 61.9 +/- 7.7 years) were assigned to receive either 400 ml/day of reduced fat ( approximately 1%) ultra-high temperature (UHT) milk containing 1000 mg of calcium plus 800 IU of vitamin D3 or to a control group receiving no additional milk. Primary endpoints were changes in BMD, serum 25(OH)D, and PTH. RESULTS: One hundred forty-nine men completed the study. Baseline characteristics between the groups were not different; mean dietary calcium and serum 25(OH)D levels were 941 +/- 387 mg/day and 77 +/- 23 nM, respectively. After 2 years, the mean percent change in BMD was 0.9-1.6% less in the milk supplementation compared with control group at the femoral neck, total hip, and ultradistal radius (range, p < 0.08 to p < 0.001 after adjusting for covariates). There was a greater increase in lumbar spine BMD in the milk supplementation group after 12 and 18 months (0.8-1.0%, p < or = 0.05), but the between-group difference was not significant after 2 years (0.7%; 95% CI, -0.3, 1.7). Serum 25(OH)D increased and PTH decreased in the milk supplementation relative to control group after the first year (31% and -18%, respectively; both p < 0.001), and these differences remained after 2 years. Body weight remained unchanged in both groups at the completion of the study. CONCLUSIONS: Supplementing the diet of men >50 years of age with reduced-fat calcium- and vitamin D3-enriched milk may represent a simple, nutritionally sound and cost-effective strategy to reduce age-related bone loss at several skeletal sites at risk for fracture in the elderly.     

Effect of calcium, vitamins K1 and D3 on bone in galactosemia

Classical galactosemia is an inherited disorder of galactose metabolism. Recently, diminished bone mineral content (BMC) in children and adolescents has been found. The aim of this study was to evaluate the effect of calcium, vitamins K(1) and D(3) supplementation on bone in children with galactosemia. A 2-year randomized, double-blind, placebo-controlled clinical trial was undertaken in which 40 children with classical galactosemia (13 males and 27 females, aged 3-17 years) were included to receive daily either 750 mg calcium, 1.0 mg vitamin K(1) and 10.0 microg vitamin D(3) or placebo. BMC of femoral neck, lumbar spine and total body and body composition data were determined by dual energy X-ray absorptiometry (DXA) at baseline and after 1 and 2 years. Diet was assessed using a food frequency questionnaire and a 3-day food diary. Biochemical measurements were determined at baseline and after 1 and 2 years. In the children receiving treatment, carboxylated osteocalcin (cOC) concentration significantly increased (P < 0.001) and undercarboxylated osteocalcin (ucOC) concentration significantly decreased (P = 0.001) when compared to the children receiving placebo. Furthermore, there was a statistically significant increase in BMC of lumbar spine (P = 0.001), lean tissue mass (LTM: P = 0.016) and fat mass (FM: P = 0.014) in the treatment group when compared to the placebo group. The significant increase in cOC and decrease in ucOC concentration in the treatment group were present in prepubertal (P < 0.001 and P = 0.006 respectively) and pubertal children (P = 0.004 and P = 0.042 respectively). The significant increase in BMC of lumbar spine in the treatment group was present only in the prepubertal children (P = 0.015). Supplementation of calcium, vitamins K(1) and D(3) given in this dose (750 mg, 1.0 mg and 10.0 mug respectively) is likely to have a role in the treatment of BMC abnormalities in galactosemia.     

Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women.

Long-term vitamin D and calcium supplementation is effective in reducing nonvertebral fractures in elderly people. Increased bone fragility caused by secondary hyperparathyroidism (sHPT) and impaired balance are known risk factors for hip fractures. The hypothesis is that short-term therapy with calcium and vitamin D may improve body sway as well as sHPT more effectively than calcium monotherapy. The effects of 8 weeks of supplementation with vitamin D (cholecalciferol) and calcium on body sway and biochemical measures of bone metabolism were measured. The sample consisted of 148 women (mean [+/-SD] age, 74 +/- 1 years) with a 25-hydroxycholecalciferol level below 50 nmol/liter. They received either 1200 mg of calcium plus 800 IU of vitamin D or 1200 mg of calcium per day. We measured intact parathyroid hormone (PTH), markers of bone turnover, and body sway before and after treatment. Falls and fractures among the participants were followed over a 1-year period. Compared with calcium mono, supplementation with vitamin D and calcium resulted in an increase in serum 25-hydroxyvitamin D of 72% (p < 0.0001), a decrease in the serum PTH of 18% ( p = 0.0432), and a decrease in body sway of 9% (p = 0.0435). The mean number of falls per subject during a 1-year follow-up period was 0.45 for the calcium mono group and 0.24 for the calcium and vitamin D group (p = 0.0346). Short-term supplementation with vitamin D and calcium improves sHPT and body sway and therefore may prevent falls and subsequent nonvertebral fractures in elderly women.     

A randomized controlled trial of vitamin D supplementation on preventing postmenopausal bone loss and modifying bone metabolism using identical twin pairs.

Vitamin D supplementation, when given with calcium, has been shown to increase bone mineral density (BMD) and reduce the incidence of hip fracture in elderly subjects. Despite its widespread use, the benefits of vitamin D supplementation in younger women and as a single agent are less clear. We performed a randomized co-twin, placebo-controlled, double-blind trial over 2 years to measure the effect of vitamin D3 supplementation on bone density and bone metabolism in young postmenopausal women. Seventy-nine monozygotic (MZ) twin pairs (mean age, 58.7 years; range, 47-70 years) were recruited. For each twin pair, one was randomized to 800 IU cholecalciferol/day for 2 years and the other was randomized to placebo. BMD was measured at the spine and hip and heel ultrasound at baseline, 12, 18, and 24 months. Samples were collected at 0, 3, and 6 months to measure serum calcium, 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), osteocalcin, and urinary deoxypyridinoline (DPD). In total, 64 pairs completed the study. No differences in baseline characteristics were seen between the groups. At 6 months, the treatment group had an increase in serum vitamin D [mean +/- SEM intrapair difference, 14.1+/-2.4 microg/liter (p < 0.001)]. There were no significant differences in other serum measurements or bone markers at 3 months or 6 months. At 24 months, no significant treatment effect was seen on BMD or calcaneal ultrasound change within pairs. Subanalysis of treatment response by vitamin D receptor (VDR) genotype revealed no significant difference in effect on BMD variables with treatment. On the basis of these results, vitamin D supplementation, on its own, cannot be recommended routinely as an osteoporosis prevention for healthy postmenopausal women with normal vitamin D levels under the age of 70 years.     

Prevalence of vertebral alterations and the effects of calcium and vitamin D supplementation on calcium metabolism and bone mineral density after gastrectomy

BACKGROUND: Bone disease is common after gastrectomy, resulting in decreased bone mass and an increased risk of fracture. No proven therapy is currently available. METHODS: Serum markers of calcium metabolism in 98 patients after partial or total gastrectomy were compared with those in 30 age- and sex-matched healthy controls. Patients with disorders of calcium metabolism were investigated by conventional radiography and single-energy computed tomography of the spine. Forty patients participated in a 1-year follow-up study to investigate the effects of vitamin D and calcium supplementation on calcium metabolism and bone mineral density. RESULTS: Altered serum markers of calcium and phosphate metabolism were observed in 77 (79 per cent) of 98 patients. Sixty (79 per cent) of these had vertebral alterations. Vertebral fractures were detected in 22 patients, grade I vertebral deformities in 50 patients, grade II deformities in 22 patients and osteopenia (Z-score less than - 1) in 30 patients. Calcium and vitamin D supplementation resulted in an increase in 25-hydroxy-vitamin D (P < 0.001), 1,25-dihydroxy-vitamin D (P = 0.048) and osteocalcin (P = 0.045), whereas levels of parathyroid hormone were decreased (P = 0.007). Bone mineral density did not change over time. CONCLUSION: Disturbances of calcium and bone metabolism are common after gastrectomy. Calcium and vitamin D supplementation normalized levels of markers of calcium metabolism and might have prevented age-related bone mass loss, although it did not increase bone mineral density after 1 year.     

Vitamin C supplement use and bone mineral density in postmenopausal women.

Vitamin C is known to stimulate procollagen, enhance collagen synthesis, and stimulate alkaline phosphatase activity, a marker for osteoblast formation. Studies of dietary vitamin C intake and the relation with bone mineral density (BMD) have been conflicting, probably because of the well-known limitations of dietary nutrient assessment questionnaires. The purpose of this study was to evaluate the independent relation of daily vitamin C supplement use with BMD in a population-based sample of postmenopausal women. Subjects were 994 women from a community-based cohort of whom 277 women were regular vitamin C supplement users. Vitamin C supplement use was validated. Daily vitamin C supplement intake ranged from 100 to 5,000 mg; the mean daily dose was 745 mg. Average duration of use was 12.4 years; 85% had taken vitamin C supplements for more than 3 years. BMD levels were measured at the ultradistal and midshaft radii, hip, and lumbar spine. After adjusting for age, body mass index (BMI), and total calcium intake, vitamin C users had BMD levels approximately 3% higher at the midshaft radius, femoral neck, and total hip (p < 0.05). In a fully adjusted model, significant differences remained at the femoral neck (p < 0.02) and marginal significance was observed at the total hip (p < 0.06). Women taking both estrogen and vitamin C had significantly higher BMD levels at all sites. Among current estrogen users, those also taking vitamin C had higher BMD levels at all sites, with marginal significance achieved at the ultradistal radius (p < 0.07), femoral neck (p < 0.07), and total hip (p < 0.09). Women who took vitamin C plus calcium and estrogen had the highest BMD at the femoral neck (p = 0.001), total hip (p = 0.05), ultradistal radius (p = 0.02), and lumbar spine. Vitamin C supplement use appears to have a beneficial effect on levels of BMD, especially among postmenopausal women using concurrent estrogen therapy and calcium supplements.     

Comparative effects of vitamin K and vitamin D supplementation on prevention of osteopenia in calcium-deficient young rats

The aim of this study was to clarify the difference in the effects of vitamin K and vitamin D supplementation on the development of osteopenia in young rats under mild calcium deficiency. Sixty female Sprague-Dawley rats, 6 weeks of age, were randomized by stratified weight method into six groups with 10 rats in each group: baseline control, 0.5% (normal) calcium diet, 0.1% (low) calcium diet, 0.1% calcium diet + vitamin K (30 mg/100 g, food intake), 0.1% calcium diet + vitamin D (25 microg/100 g, food intake), and 0.1% calcium diet + K + D. After 10 weeks of feeding, serum calcium, 25-hydroxyvitamin D(3) [25 (OH) D(3)], 1,25-dihydroxyvitamin D(3) [1,25 (OH)(2) D(3)], and parathyroid hormone (PTH) levels were measured, and intestinal calcium absorption and renal calcium reabsorption were evaluated. Bone histomorphometric analyses were performed on cortical bone of the tibial shaft and cancellous bone of the proximal tibia. Calcium deficiency induced hypocalcemia, increased serum PTH and 1,25 (OH)(2) D(3) levels with decreased serum 25 (OH) D(3) level, stimulated intestinal calcium absorption and renal calcium reabsorption, and reduced maturation-related cortical bone gain as a result of decreased periosteal bone gain and enlarged marrow cavity but did not significantly influence maturation-related cancellous bone gain. Vitamin K supplementation in calcium-deficient rats stimulated renal calcium reabsorption, retarded the abnormal elevation of serum PTH level, increased maturation-related cancellous bone gain, and retarded the reduction in maturation-related cortical bone gain. On the other hand, vitamin D supplementation in calcium-deficient rats stimulated intestinal calcium absorption via increased serum 1,25 (OH)(2) D(3) level with prevention of the abnormal elevation of serum PTH level, prevented hypocalcemia, reduced the maturation-related cancellous bone gain, and prevented the reduction in periosteal bone gain and enhanced enlargement of the marrow cavity with no significant effect on the reduction in maturation-related cortical bone gain. However, no synergistic effect of vitamin K and vitamin D on intestinal calcium absorption, renal calcium reabsorption, and cancellous and cortical bone mass was found. This study shows the differential effects of vitamin K and vitamin D supplementation on the development of osteopenia in young rats under mild calcium deficiency. Vitamin K supplementation stimulates renal calcium reabsorption, increases maturation-related cancellous bone gain, and retards the reduction in maturation-related cortical bone gain, whereas vitamin D supplementation stimulates intestinal calcium absorption and prevents the reduction in maturation-related periosteal bone gain by inducing accumulation of calcium from cancellous and endocortical bone.     

Vitamin D Supplementation After Parathyroidectomy: Effect on Bone Mineral Density—A Randomized Double‐Blind Study

Patients with primary hyperparathyroidism (PHPT) have higher bone turnover, lower bone mineral density (BMD), and an increased risk of fractures. They also have a high incidence of low vitamin D levels (25‐OH‐vitamin D <50 nmol/L) that could worsen the negative effect on the bone. In this double‐blinded clinical trial, 150 patients with PHPT were randomized, after successful parathyroidectomy (PTX), to 1‐year daily treatment with either cholecalciferol 1600 IU and calcium carbonate 1000 mg (D +) or calcium carbonate alone (D–). BMD was measured in the lumbar spine, femoral neck, total hip, distal and 33% radius using dual‐energy X‐ray absorptiometry (DXA) before surgery and after 1 year of study medication. Median age was 60 (range 30–80) years and there were 119 (79%) women and 31 (21%) men; 76% had 25‐OH‐D <50 nmol/L before PTX and 50% had persistent elevated parathyroid hormone (PTH) 6 weeks after PTX. A similar increase in BMD in the lumbar spine, femoral neck, and total hip was observed in both groups (D + : 3.6%, 3.2%, and 2.7%, p < 0.001, respectively; and D–: 3.0%, 2.3%, and 2.1%, respectively, p < 0.001). Patients with vitamin D supplementation also increased their BMD in distal radius (median 2.0%; interquartile range, ?1.7% to 5.4%; p = 0.013). The changes in BMD, especially in the hips, were correlated to the baseline concentrations of PTH, ionized calcium, and bone markers (p < 0.001). A benefit from vitamin D substitution was observed among patients with a persistent postoperative PTH elevation, who also improved their BMD at 33% radius and radius ultradistal (p < 0.05). In conclusion, except for a minor improvement of radius BMD, our data show no beneficial effect on BMD or bone turnover markers of vitamin D supplementation after PTX. Preoperative PTH seems to have the strongest association with improvement in BMD. © 2014 American Society for Bone and Mineral Research.     

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.     

Peripheral Bone Mass is Not Affected by Winter Vitamin D Deficiency in Children and Young Adults from Ushuaia

Low vitamin D levels in elderly people are associated with reduced bone mass, secondary hyperparathyroidism, and increased fracture risk. Its effect on the growing skeleton is not well known. The aim of this study was to evaluate the possible influence of chronic winter vitamin D deficiency and higher winter parathyroid hormone (PTH) levels on bone mass in prepubertal children and young adults. The study was carried out in male and female Caucasian subjects. A total of 163 prepubertal children (X age ± 1 SD: 8.9 ± 0.7 years) and 234 young adults (22.9 ± 3.6 years) who had never received vitamin D supplementation were recruited from two areas in Argentina: (1)Ushuaia (55° South latitude), where the population is known to have low winter 25OHD levels and higher levels of PTH in winter than in summer, and (2)Buenos Aires (34°S), where ultraviolet (UV) radiation and vitamin D nutritional status in the population are adequate all year round. Bone mineral content (BMC) and bone mineral density (BMD) of the ultradistal and distal radius were measured in the young adults. Only distal radius measurements were taken in the children. Similar results were obtained in age-sex matched groups from both areas. The only results showing significant difference corresponded to comparison among the Ushuaian women: those whose calcium (Ca) intake was below 800 mg/day presented lower BMD and BMC values than those whose Ca intake was above that level (0.469 ± 0.046 versus 0.498 ± 0.041 g/cm², P < 0.02; 3.131 ± 0.367 versus 3.339 ± 0.386 g, P < 0.05, respectively). In conclusion, peripheral BMD and BMC were similar in children and young adults from Ushuaia and Buenos Aires in spite of the previously documented difference between both areas regarding UV radiation and winter vitamin D status. BMD of axial skeletal areas as well the concomitant effect of a low Ca diet and vitamin D deficiency on the growing skeleton should be studied further. Received: 7 June 1999 / Accepted: 22 March 2000     

Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency

Significant reduction in bone mineral density (BMD) occurs in patients with Parkinson's disease (PD), correlating with immobilization and with vitamin D deficiency, and increasing the risk of hip fracture, especially in elderly women. As a biological indicator of compromised vitamin K status, an increased serum concentration of undercarboxylated osteocalcin (Oc) has been associated with reduced BMD in the hip and an increased risk of fracture in otherwise healthy elderly women. We evaluated treatment with vitamin K(2) (menatetrenone; MK-4) in maintaining BMD and reducing the incidence of nonvertebral fractures in elderly female patients with PD. In a random and prospective study of PD patients, 60 received 45 mg of MK-4 daily for 12 months, and the remaining 60 (untreated group) did not. At baseline, patients of both groups showed vitamin D and K(1) deficiencies, high serum levels of ionized calcium, and glutaminic residue (Glu) Oc, and low levels of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25-(OH)(2)D], indicating that immobilization-induced hypercalcemia inhibits renal synthesis of 1,25-(OH)(2)D and compensatory PTH secretion. BMD in the second metacarpals increased by 0.9% in the treated group and decreased by 4.3% in the untreated group (p < 0.0001). Vitamin K(2) level increased by 259.8% in the treated group. Correspondingly, significant decreases in Glu Oc and calcium were observed in the treated group, in association with an increase in both PTH and 1,25-(OH)(2)D. Ten patients sustained fractures (eight at the hip and two at other sites) in the untreated group, and one hip fracture occurred among treated patients (p = 0.0082; odds ratio = 11.5). The treatment with MK-4 can increase the BMD of vitamin D- and K-deficient bone by increasing vitamin K concentration, and it can also decrease calcium levels through inhibition of bone resorption, resulting in an increase in 1,25-(OH)(2)D concentration.     

Vitamin K Treatment Reduces Undercarboxylated Osteocalcin but Does Not Alter Bone Turnover,Density, or Geometry in Healthy Postmenopausal North American Women

Low vitamin K status is associated with low BMD and increased fracture risk. Additionally, a specific menaquinone, menatetrenone (MK4), may reduce fracture risk. However, whether vitamin K plays a role in the skeletal health of North American women remains unclear. Moreover, various K vitamers (e.g., phylloquinone and MK4) may have differing skeletal effects. The objective of this study was to evaluate the impact of phylloquinone or MK4 treatment on markers of skeletal turnover and BMD in nonosteoporotic, postmenopausal, North American women. In this double‐blind, placebo‐controlled study, 381 postmenopausal women received phylloquinone (1 mg daily), MK4 (45 mg daily), or placebo for 12 mo. All participants received daily calcium and vitamin D₃ supplementation. Serum bone‐specific alkaline phosphatase (BSALP) and n‐telopeptide of type 1 collagen (NTX) were measured at baseline and 1, 3, 6, and 12 mo. Lumbar spine and proximal femur BMD and proximal femur geometry were measured by DXA at baseline and 6 and 12 mo. At baseline, the three treatment groups did not differ in demographics or study endpoints. Compliance with calcium, phylloquinone, and MK4 treatment was 93%, 93%, and 87%, respectively. Phylloquinone and MK4 treatment reduced serum undercarboxylated osteocalcin but did not alter BSALP or NTX. No effect of phylloquinone or MK4 on lumbar spine or proximal femur BMD or proximal femur geometric parameters was observed. This study does not support a role for vitamin K supplementation in osteoporosis prevention among healthy, postmenopausal, North American women receiving calcium and vitamin D supplementation.     

Low bone density and bone metabolism alterations in Duchenne muscular dystrophy: response to calcium and vitamin D treatment

Summary

Boys with Duchenne muscular dystrophy often have reduced bone mass and increased fracture risk. In this prospective study on 33 patients, calcifediol (25-OH vitamin D₃) plus adjustment of dietary calcium to the recommended dose reduced bone resorption, corrected vitamin D deficiency, and increased bone mass in about two-thirds of cases.

Introduction

Low BMC and BMD and bone metabolism alterations are frequent in boys with Duchenne muscular dystrophy (DMD), especially now that long-term glucocorticosteroid (GC) treatment is the standard of care. This prospective study was designed to evaluate the effects of a first-line treatment (25-OH vitamin D₃ [calcifediol] plus adjustment of dietary calcium to the recommended daily dose) on bone.

Methods

Thirty-three children with DMD on GC treatment were followed for 3?years: one of observation and two of treatment. Main outcome: spine and total body BMC and BMD increase; secondary outcome: changes in bone turnover markers (C-terminal [CTx] and N-terminal [NTx] telopeptides of procollagen type I; osteocalcin [OC]).

Results

During the observation year, BMC and BMD decreased in all patients. At baseline and after 12?months, serum CTx and urinary NTx were higher than normal; OC and parathyroid hormone at the upper limit of normal; 25-OH vitamin D₃ significantly lower than normal. After 2?years of calcifediol and calcium-rich diet, BMC and BMD significantly increased in over 65% of patients, and bone metabolism parameters and turnover markers normalized in most patients (78.8%). During the observation year, there were four fractures in four patients, while during the 2?years of treatment there were two fractures in two patients.

Conclusions

Calcifediol plus adequate dietary calcium intake seems to be an effective first-line approach that controls bone turnover, corrects vitamin D deficiency, and increases BMC and BMD in most patients with DMD. Lack of response seems related to persistently high bone turnover.     

Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K<Subscript>2</Subscript> in postmenopausal women

Alendronate decreases the risk of femoral neck fracture by suppressing bone turnover, and also decreases the serum total osteocalcin level. A low serum carboxylated osteocalcin level or high undercarboxylated osteocalcin level could be risk factors for femoral neck fracture. Vitamin K mediates the carboxylation of osteocalcin, but the effect of alendronate therapy with or without vitamin K₂ supplementation remains unknown. Forty-eight postmenopausal women were enrolled in a 1-year prospective randomized trial and assigned to alendronate monotherapy (5 mg/day) (group A, n = 26) or vitamin K₂ (45 mg/day) plus alendronate (5 mg/day) (group AK, n = 22). Bone mineral density was measured by dual-energy X-ray absorptiometry at 0 and 12 months; bone turnover parameters were measured at 0, 3, and 12 months. Four patients discontinued alendronate therapy, and we analyzed the remaining 44 patients (23 in group A and 21 in group AK) who completed 1 year of treatment. Alendronate decreased undercarboxylated osteocalcin; carboxylated osteocalcin was not affected. Addition of vitamin K₂ enhanced the decrease of undercarboxylated osteocalcin levels and led to a greater increase of femoral neck bone mineral density. Alendronate monotherapy does not decrease carboxylation of osteocalcin, and combination of vitamin K₂ and alendronate brings further benefits on both osteocalcin carboxylation and BMD of femoral neck in postmenopausal women with osteoporosis.     

Bone Turnover and the Response to Alendronate Treatment in Postmenopausal Osteoporosis

This study investigated whether bone turnover influences the response to alendronate in women with postmenopausal osteoporosis. One hundred postmenopausal osteoporotic women were randomized to receive either alendronate (10 mg/day) plus calcium (1000 mg/day) (n = 50) or calcium alone (n = 50). Vertebral and radial bone density, measured by DXA, and markers of bone turnover were assessed at baseline and after 1 and 2 years. At the end of treatment, alendronate users showed an increase of 5.0% and 2.3%, respectively, at the lumbar spine and ultradistal radius; in the group treated only with calcium, bone mineral density (BMD) decreased by 1.6% at the lumbar spine and 1.3% at the ultradistal radius. The difference between the two groups was significant (P < 0.001). The patients were divided into high (HT) or low (LT) bone turnover groups, as assessed by 24-hour whole body retention (WBR%) of ^99mTc-methylene-diphosphonate. The response to alendronate treatment was greater in HT patients compared with LT patients. In fact, at the end of the study period, BMD at the lumbar spine had increased by 7.9% in HT patients and by 3.0% in LT patients; the difference between the two groups was significant (P < 0.001). No significant difference between the two groups was found for BMD at the ultradistal radius. In conclusion, the present study demonstrates that 2-year treatment with alendronate has highly positive effects on bone mass at both the lumbar spine and ultradistal radius. The increase in bone mass, especially at the axial level, is influenced by bone turnover. Therefore, the evaluation of bone turnover may be useful in predicting the response to alendronate treatment. Received: 23 April 1998 / Accepted: 10 June 1999     

Determinants of Bone Mass and Bone Geometry in Adolescent and Young Adult Women

Bone mass and bone geometry are considered to have independent effects on bone strength. The purpose of this study was to obtain data on bone mass and geometry in young female populations and how they are influenced by body size and lifestyle factors. In a cross-sectional, observational study in six European countries, 1116 healthy Caucasian girls aged 11–15 and 526 women aged 20–23 participated. Their radius was scanned at the ultradistal site and at a site approximately 30% of the radius length from the distal end with dual energy X-ray absorptiometry (DXA). The following parameters were assessed from the scans: bone mineral content (BMC), bone mineral density (BMD), cortical wall thickness (CWT), middistal diameter (D), cortical index (CI = 2CWT/D), and the Breaking Bending Resistance Index (BBRI = (D⁴− [D-CWT]⁴)/D). Calcium intake was assessed by 3-day food records and physical activity by questionnaire. Body size parameters were measured by anthropometry. All parameters showed an increasing trend with pubertal stage and age, except for physical activity and calcium intake. BMC and BMD were relatively more dependent on body weight and age at menarche, whereas variation in D and the mechanical index BBRI was better explained by differences in height and grip strength. CI and CWT were relatively independent of variation in body size, whereas BMC and BBRI especially were explained for a substantial proportion (25–33% in the young adults) by body size parameters. Dietary intake of calcium and level of physical activity seem to contribute little to variation in bone parameters. Received: 1 October 1998 / Accepted: 26 July 1999     

Bone and body composition of children and adolescents with repeated forearm fractures.

DXA measurements in 90 children and adolescents with repeated forearm fractures showed reduced ultradistal radius BMC and BMD values and elevated adiposity, suggesting site-specific bone weakness and high body weight increase fracture risk. Symptoms to cow milk, low calcium intakes, early age of first fracture, and overweight were over-represented in the sample. INTRODUCTION: Although many apparently healthy children fracture their forearms repeatedly during growth, no previous studies of their bone health and body composition have been undertaken. Nor has the prevalence of established risk factors for fracture in such a population been assessed. MATERIALS AND METHODS: Ninety children and adolescents (47 girls and 43 boys) 5-19 years of age, who had experienced at least two fractures of the forearm, were studied. Bone size and mineralization were assessed using DXA at the ultradistal radius, one-third radius, neck of femur, hip trochanter, lumbar spine, and total body. Total body lean mass and fat mass were also determined. The prevalence of six risk factors for fracture were also examined, and their influence on ultradistal BMC Z scores was assessed. RESULTS: Participants experienced 295 fractures (74.9% forearm). Children with an early age of first fracture had higher rates of fracture per l00 years of exposure than those fracturing later. Four risk factors for fracture were over-represented in observed versus expected percentages: early age of first fracture (27.7% versus 11.3%), adverse symptoms to cow milk (22.2% versus 6.7%), low dietary calcium intake (20% versus 4.5%), and overweight (33.3% versus 15.5%). However, physical activity levels were similar to the reference population. Z scores for BMC and BMD were reduced, particularly at the ultradistal radius, whereas Z scores for weight, body mass index, fat mass, and body fat percentage were increased. Mean (SD) BMC Z scores were lowest at the ultradistal radius, -0.66 (1.22), where symptoms to milk were associated with reduced values (p < 0.009) and overweight with increased values (p < 0.003). CONCLUSIONS: Our results suggest site-specific weakness and high body weight contribute to fracture risk in children and adolescents who fracture their forearms repeatedly. These findings are consonant with work showing adult Colles fractures increase as ultradistal radius BMD falls and with evidence that overweight children and adolescents are fracture prone.     

Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women.

Osteocalcin, also called bone gla protein, is a unique noncollagenous protein of the extracellular matrix of bone that circulates in blood. Oseteocalcin contains three residues of the vitamin K-dependent gamma-carboxyglutamic acid (gla) responsible for the affinity of osteocalcin for bone mineral. In animals treated with the vitamin K antagonist warfarin, the osteocalcin content of bone is markedly reduced and the fraction of osteocalcin released into the circulation is increased. Most studies have shown that osteocalcin increases with aging in women, reflecting an increase in bone turnover, especially after the menopause. To determine if this increase in osteocalcin could be associated with impaired carboxylation, we measured total and noncarboxylated osteocalcin in the serum of 72 women of various ages: 22 premenopausal (31 +/- 7 years old), 20 early postmenopausal (54 +/- 3 years), and 30 elderly women (85 +/- 8 years). As previously reported, total serum osteocalcin was significantly increased in early postmenopausal and elderly women. Noncarboxylated serum osteocalcin was slightly increased in early postmenopausal women (0.95 +/- 0.4 versus 0.65 +/- 0.5 ng/ml in premenopausal women), markedly elevated in elderly women (1.59 +/- 1.1 ng/ml, p less than 0.001), and correlated with age (r = 0.47, p less than 0.001). Elderly women had values of the same magnitude as in 10 patients on chronic warfarin therapy (1.94 +/- 1.1 ng/ml). As a consequence, the increase in carboxylated serum osteocalcin was significant in early postmenopausal women but not in elderly women. Serum levels of vitamin K1 and of menaquinones 6, 7, and 8 were measured in some of the young and elderly women.(ABSTRACT TRUNCATED AT 250 WORDS)