Vitamin D is widely used in osteoporosis treatment, although the optimal dose is not known. This 1-year clinical study among 297 women aged 50-80 years old showed that a vitamin D(3) dose of 6,500 IU/day was not better than the standard dose of 800 IU/day in improving bone mineral density (BMD) in the hip and spine.

BACKGROUND

The purpose of this study was to determine whether a high dose of vitamin D(3) was better than the standard dose in improving BMD and reducing bone turnover in postmenopausal women with reduced bone mass.

METHODS

The study was a 1-year randomized double-blind controlled trial comparing high-dose vitamin D(3) with the standard dose. Postmenopausal women (n = 297) with a BMD T-score ≤ -2.0 in either lumbar spine (L2-4) or total hip were included and randomized to 6,500 IU vitamin D(3)/day (20,000 IU twice per week + 800 IU/day) or 800 IU vitamin D(3)/day (placebo twice per week + 800 IU/day). Both groups were given 1,000 mg elemental calcium/day. The primary endpoint was a change in BMD in total hip and lumbar spine (L2-4).

RESULTS

After 1 year, serum 25-hydroxyvitamin D (25(OH)D) increased [mean (SD)] from 71 (23) to 185 (34) nmol/l and from 71 (22) to 89 (17) nmol/l in the high- and standard-dose vitamin D groups, respectively. BMD at all measurement sites was unchanged or slightly improved with no significant differences between the groups. Although bone turnover was reduced in both groups, the more pronounced reduction in serum levels of the bone formation marker P1NP in the standard-dose group may indicate that this treatment was more efficient. Adverse events did not differ between the groups.

CONCLUSIONS

One year treatment with 6,500 IU vitamin D(3)/day was not better than 800 IU/day regarding BMD in vitamin D-replete postmenopausal women with reduced bone mass and was less efficient in reducing bone turnover.

OBJECTIVE

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures and thiazolidinediones (TZDs) increase this risk. TZDs stimulate the expression of sclerostin, a negative regulator of bone formation, in vitro. Abnormal sclerostin production may, therefore, be involved in the pathogenesis of increased bone fragility in patients with T2DM treated with TZDs.

METHODS

We measured serum sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and carboxy-terminal cross-linking telopeptide of type I collagen (CTX) in 71 men with T2DM treated with either pioglitazone (PIO) (30 mg once daily) or metformin (MET) (1000 mg twice daily). Baseline values of sclerostin and P1NP were compared with those of 30 healthy male controls.

RESULTS

Compared with healthy controls, patients with T2DM had significantly higher serum sclerostin levels (59.9 vs 45.2 pg/ml, P<0.001) but similar serum P1NP levels (33.6 vs 36.0 ng /ml, P=0.39). After 24 weeks of treatment, serum sclerostin levels increased by 11% in PIO-treated patients and decreased by 1.8% in MET-treated patients (P=0.018). Changes in serum sclerostin were significantly correlated with changes in serum CTX in all patients (r=0.36, P=0.002) and in PIO-treated patients (r=0.39, P=0.020), but not in MET-treated patients (r=0.17, P=0.31).

CONCLUSIONS

Men with T2DM have higher serum sclerostin levels than healthy controls, and these levels further increase after treatment with PIO, which is also associated with increased serum CTX. These findings suggest that increased sclerostin production may be involved in the pathogenesis of increased skeletal fragility in patients with T2DM in general and may specifically contribute to the detrimental effect of TZDs on bone.

Strenuous physical activity in young individuals has an important effect on both bone mass and bone turnover but the effect of moderate physical activity in adults remains uncertain. In a large cohort (N = 530) of healthy premenopausal women, bone formation markers (osteocalcin and N-terminal propeptide of type 1 procollagen [P1NP]), but not serum C-telopeptide of type 1 collagen (sCTX), were found to be significantly associated with the level of physical activity, and this association remained significant after adjusting the data (ANCOVA) by age and body mass index. Mean spine and hip bone mineral density (BMD) values were positively associated with physical activity but this was statistically significant (P = 0.050) only for adjusted values of spine BMD. Twenty-four healthy sedentary premenopausal women, subscribing to participate in a community exercise program lasting a month, and 18 age-matched controls were included in the longitudinal study. Serum osteocalcin and P1NP, but not sCTX, rose significantly, by ca. 25%, only in the active group after a month of exercise. The changes in the two bone formation markers remained statistically significant for values adjusted for body weight, which fell significantly in the exercise group. In conclusion, both the cross-sectional and the longitudinal parts of our study demonstrate that even minor changes in physical activity are associated with a clear effect on bone formation markers.

BACKGROUND

The role of sclerostin as a key regulator of bone formation remains unknown after Roux-en-Y gastric bypass (RYGB) or laparoscopic sleeve gastrectomy (SG).

OBJECTIVE

The study objectives were evaluation of sclerostin and Dickkopf-1 (DKK-1) serum levels after surgery and correlations with bone turnover markers (P1NP, CTX), parathyroid hormone (iPTH) and areal bone mineral density (BMD), changes at total body, lumbar spine and total hip.

METHODS

This was a prospective observational single-center two-arm study in premenopausal women with acute adipositas over 24 months.

METHODS

Participants were 52 premenopausal women (40 ± 8 years, BMI 43.4) after RYGB and 38 premenopausal women (41 ± 7 years, BMI 45.7) after SG.

METHODS

Prior to surgery and 1, 3, 6, 9, 12, 18, and 24 months after surgery sclerostin, DKK-1, CTX, P1NP levels and BMD were measured.

RESULTS

Sclerostin, CTX and (to a lesser extent) P1NP increased after surgery and remained elevated during the entire study period (P < 0.001). DKK-1 declined during months 3-9 (P < 0.005) and then remained unchanged, serum phosphate continuously increased (P < 0.001), iPTH remained within the upper normal limit. Sclerostin increases were significantly positively correlated with CTX and P1NP increases and negatively correlated with BMD loss. BMD independently declined regardless of RYGB and SG. Elevations of sclerostin, CTX, P1NP, and phosphate, but not DKK-1 and iPTH, were significant discriminating factors for BMD loss (AUC 0.920).

CONCLUSIONS

Rapid and sustained increases of sclerostin, CTX, and to a lesser extent, P1NP cause an increase in bone metabolism and result in BMD loss at all skeletal sites.

The reference ranges of bone turnover markers (BTMs) were important during the treatment of osteoporosis, and the associations with bone mineral density (BMD) were controversial. The aim of this study was to establish the reference ranges of N-terminal procollagen of type l collagen (P1NP), osteocalcin (OC), and beta C-terminal cross-linked telopeptides of type I collagen ( β -CTX) in Shanghai area and to investigate the relationships between BTMs and BMD in postmenopausal women. 2,799 subjects recruited in Shanghai City were measured BTMs to establish the reference ranges. Additional 520 healthy postmenopausal women were also measured BTMs, these women measured BMD in addition. BTMs were measured using the Roche electrochemiluminescence system. We used the age range of 35 to 45-year-olds to calculate reference intervals. The reference range of OC was 4.91 to 13.90 ng/mL for women and 5.58 to 16.57 ng/mL for men, P1NP was 13.72 to 32.90 ng/mL for women and 16.89 to 42.43 ng/mL for men, and β -CTX was 0.112 to 0.210 ng/mL for women and 0.100 to 0.378 ng/mL for men. BTMs significantly negatively correlated with lumbar spine and femoral and total hip in postmenopausal women (Betastd = -0.157 ~ -0.217, P < 0.001). We established the normal reference ranges of P1NP, OC, and β -CTX in the Shanghai area. This study also found that BTMs correlated with BMD and suggested that BTMs were the key determining factors of early BMD decreases.

Current guidelines recommend weight-bearing activities, preferably strength training for improving skeletal health in patients with osteoporosis. What type of strength training that is most beneficial for these patients is not established. Maximal strength training (MST) is known to improve 1-repetition maximum (1RM) and rate of force development (RFD), which are considered as important covariables for skeletal health. Squat exercise MST might serve as an effective intervention for patients with low bone mass. We hypothesized that 12 weeks of squat exercise MST would improve 1RM and RFD in postmenopausal women with osteoporosis or osteopenia and that these changes would coincide with improved bone mineral density (BMD) and bone mineral content (BMC), and serum markers of bone metabolism. The participants were randomized to a training group (TG, n = 10) or control group (CG, n = 11). The TG underwent 12 weeks of supervised squat exercise MST, 3 times a week, with emphasis on rapid initiation of the concentric part of the movement. The CG was encouraged to follow current exercise guidelines. Measurements included 1RM, RFD, BMD, BMC, and serum bone metabolism markers; type 1 collagen amino-terminal propeptide (P1NP) and type 1 collagen C breakdown products (CTX). At posttest, 8 participants remained in each group for statistical analyses. The TG improved the 1RM and RFD by 154 and 52%, respectively. Lumbar spine and femoral neck BMC increased by 2.9 and 4.9%. The ratio of serum P1NP/CTX tended to increase (p = 0.09), indicating stimulation of bone formation. In conclusion, squat exercise MST improved 1RM, RFD, and skeletal properties in postmenopausal women with osteopenia or osteoporosis. The MST can be implemented as a simple and effective training method for patients with reduced bone mass.

Few year-long vitamin D supplementation trials exist that match seasonal changes. The aim of this study was to determine whether daily oral vitamin D3 at 400 IU or 1000 IU compared with placebo affects annual bone mineral density (BMD) change in postmenopausal women in a 1-year double-blind placebo controlled trial in Scotland. White women aged 60 to 70 years (n = 305) were randomized to one of two doses of vitamin D or placebo. All participants started simultaneously in January/February 2009, attending visits at bimonthly intervals with 265 (87%) women attending the final visit and an additional visit 1 month after treatment cessation. BMD (Lunar iDXA) and 1,25-dihydroxyvitamin D[1,25(OH)2 D], N-terminal propeptide of type 1 collagen [P1NP], C-terminal telopeptide of type I collagen [CTX], and fibroblast growth factor-23 [FGF23] were measured by immunoassay at the start and end of treatment. Circulating PTH, serum Ca, and total 25-hydroxyvitamin D [25(OH)D] (latter by tandem mass spectrometry) were measured at each visit. Mean BMD loss at the hip was significantly less for the 1000 IU vitamin D group (0.05% ± 1.46%) compared with the 400 IU vitamin D or placebo groups (0.57% ± 1.33% and 0.60% ± 1.67%, respectively) (p < 0.05). Mean (± SD) baseline 25(OH)D was 33.8 ± 14.6 nmol/L; comparative 25(OH)D change for the placebo, 400 IU, and 1000 IU vitamin D groups was -4.1 ± 11.5 nmol/L, +31.6 ± 19.8 nmol/L, and +42.6 ± 18.9 nmol/L, respectively. Treatment did not change markers of bone metabolism, except for a small reduction in PTH and an increase in serum calcium (latter with 1000 IU dose only). The discordance between the incremental increase in 25(OH)D between the 400 IU and 1000 IU vitamin D and effect on BMD suggests that 25(OH)D may not accurately reflect clinical outcome, nor how much vitamin D is being stored.

The role of B cells in inflammatory bone formation and resorption is controversial. We investigated this in patients with rheumatoid arthritis (RA) treated with rituximab, a B-cell depleting antibody. We found a significant suppression in bone turnover, possibly a direct effect or as a consequence of a reduction in inflammation and disease activity.

BACKGROUND

RA is the most prevalent inflammatory joint disease, in which B cells play an important role. However, the role of B cells in bone turnover is controversial and RA subjects treated with rituximab, a B-cell depleting monoclonal antibody, provide an ideal model for determining the role of B cells in inflammatory bone resorption.

METHODS

Serum from 46 RA patients, collected pre- and post-rituximab therapy, was analysed for biomarkers of bone turnover (procollagen type I amino-terminal propeptide [P1NP], osteocalcin, β-isomerised carboxy-terminal telopeptide of type 1 collagen [βCTX] and osteoprotegerin [OPG]).

RESULTS

A significant decrease in bone resorption was observed 6 months after rituximab (median change βCTX -50 ng/L, 95%CI -136, -8 p < 0.001, this equates to -37%; 95%CI -6, -49), mirrored by a reduction in disease activity. Similarly, there was a significant increase in P1NP, a marker of bone formation (median change P1NP 5.0 μg/L, 95%CI -1.0, 11.2, p = 0.02; 13%; 95%CI -3, 39), but no significant change in osteocalcin or OPG levels. The percentage change from baseline of βCTX in a subgroup of patients (not on prednisolone or bisphosphonate) was significantly correlated with the percentage reduction in DAS28 score (r (s) = 0.570, p = 0.014).

CONCLUSIONS

In conclusion, we have found that B-cell depletion increases bone formation and decreases bone resorption in RA patients; this may be a direct effect on osteoblasts and osteoclasts, respectively, and be at least partially explained by the decreased inflammation and disease activity.

Annual intravenous administration of 5 mg of zoledronate decreases fracture risk over 3 years. The optimal dosing interval of 5 mg of zoledronate is not known. In order to determine the duration of the antiresorptive action of a single 5-mg dose of intravenous zoledronate, we conducted a 3-year double-blind, randomized, placebo-controlled trial in a volunteer sample of 50 postmenopausal women with osteopenia. The coprimary endpoints were the bone turnover markers β-C-terminal telopeptide of type I collagen (β-CTX) and serum procollagen type-I N-terminal propeptide (P1NP). Secondary endpoints were bone mineral density (BMD) at the lumbar spine, total hip, and total body. After 3 years, mean (95% confidence interval) levels of serum β-CTX and P1NP were 44% (27-60) and 40% (24%-56%) lower in the zoledronate group (p < .001 versus placebo for each marker). BMD was higher in the zoledronate group than in the placebo group by an average of 6.8% (4.6%-9.1%) at the lumbar spine, 4.0% (1.8%-6.3%) at the total hip, and 2.0% (0.9%-3.0%) at the total body (p < .001 for each skeletal site). Between-group differences in markers of bone turnover and BMD were stable from 12 to 36 months. These data demonstrate that the antiresorptive effects of a single 5-mg dose of zoledronate are sustained for 3 years; clinical trials to investigate the antifracture efficacy of dosing intervals longer than 1 year are justified.

Bone turnover markers (BTM) progressively decrease in young adult women. This might be linked to changes in insulin-like growth factor-1 (IGF-I). Four serum BTMs [serum C-telopeptide of type 1 collagen (CTX), osteocalcin (OC), N-terminal propeptide of type 1 procollagen (P1NP), and bone alkaline phosphatase (bone AP)], serum calcium (sCa), phosphate (sPO(4)), magnesium, 25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone (PTH) and IGF-I were measured in 531 young healthy premenopausal women aged 20-50 years participating in the BONTURNO study. In all subjects bone mineral density (BMD) was measured at the spine and at the hip by dual-energy X-ray densitometry. Hip BMD, IGF-I, the four BTMs, sCa and sPO(4) progressively decreased with advancing age and this was associated with proportional increases in PTH. IGF-I levels were significantly and positively correlated with sCa, sPO(4), CTX, OC, P1NP, bone AP, spine BMD, femoral neck BMD and total hip BMD and negatively with age, BMI and serum PTH. When the IGF-I levels were adjusted for age and BMI, the only correlations maintaining a statistical significance were those with serum PTH, P1NP and bone AP. These associations were weak and IGF-I accounted for a only a small proportion of the BTM variance. The mean, age-adjusted IGF-I values were significantly higher in women practicing physical exercises for more then 60 min per week than in sedentary women. In conclusion, in this study we provide evidence of an association between the age-related decline in IGF-I with the progressive decrease in bone formation markers in premenopausal women.

BACKGROUND

Daily PTH administration increases bone mineral density (BMD) and reduces fracture risk. However, cost and compliance significantly limit clinical use.

OBJECTIVE

Our objective was to determine whether less frequent PTH administration increases lumbar spine BMD.

METHODS

Fifty postmenopausal women ages 45-70 yr with femoral neck BMD T-score between -1.0 and -2.0 participated in a double-blind, randomized, placebo-controlled trial at St. Joseph Hospital, Bangor, ME.

METHODS

Subjects received sc injections of daily PTH(1-84) (100 mug) or placebo for 1 month, followed by weekly injections (PTH or placebo) for 11 months.

RESULTS

Change in lumbar spine dual-energy x-ray absorptiometry areal BMD (primary) was assessed. Secondary outcomes included volumetric BMD at spine and hip by quantitative computed tomography, trabecular bone microarchitecture by magnetic resonance imaging of distal radius, and biochemical bone turnover markers.

RESULTS

At 12 months, lumbar spine areal BMD increased 2.1% in PTH-treated women compared with placebo (P = 0.03). Vertebral trabecular volumetric BMD increased 3.8% in PTH-treated women compared with placebo group (P = 0.08). PTH-treated women also had higher distal radial trabecular bone volume, number, and thickness compared with placebo-treated women (P < 0.04). After 1 month of daily PTH, N-terminal propeptide of type I collagen (P1NP) was markedly increased compared with placebo (P < 0 .0001), and a difference persisted, although lessened, throughout the study. Bone resorption indices were unchanged in PTH-treated women and were reduced in the placebo group.

CONCLUSIONS

Once-weekly PTH after 1 month of daily treatment increases spine BMD, radial trabecular bone, and bone formation markers in postmenopausal women. These results suggest that less frequent alternatives to daily PTH dosing for 2 yr could be effective. Additional studies are required to define the optimal frequency of PTH administration.

BACKGROUND

The aim of this exploratory study was to establish whether we could improve skeletal health with a physiological regimen of SSR in young women with premature ovarian failure (POF).

METHODS

In an open-label randomized controlled crossover trial, 34 women with POF were randomized to 4-week cycles of pSSR (transdermal oestradiol, 100 μg daily for week 1, 150 μg for weeks 2-4; vaginal progesterone, 200 mg twice daily for weeks 3-4) or standard hormone replacement treatment (sHRT) (oral ethinyloestradiol 30 μg and 1·5 mg norethisterone daily for weeks 1-3, week 4 'pill-free') for 12 months. Bone mineral density (BMD) was measured by DEXA at study entry and after each 12-month treatment period. Blood samples for hormones and markers of bone formation (bone alkaline phosphatase, BALP and type I collagen N-terminal propeptide, PINP) and bone resorption (CrossLaps) were collected pre-/postwashout and after 3, 6 and 12 months of each treatment.

RESULTS

Eighteen women, mean 27 (range 19-39) years, completed the study. Both regimens caused similar suppression of LH and FSH. Mean baseline lumbar spine BMD z-score was -0·89 (95% CI -1·27 to -0·51) and increased by +0·17 (CI +0·07 to +0·27) in response to pSSR (P = 0·003), compared with +0·07 (CI -0·03 to +0·18) during standard HRT (P = 0·2). During pSSR, the increment in lumbar spine BMD z-score was related positively to oestradiol (r = +0·49, P = 0·04) and inversely to FSH (r = -0·65, P = 0·004). Bone formation markers, BALP and P1NP increased in the pSSR arm (anova P < 0·001) but decreased in the sHRT arm (P < 0·01). Both treatments suppressed the bone resorption marker, CrossLaps (P < 0·001).

CONCLUSIONS

We conclude that pSSR over 12 months has a beneficial affect on bone mass acquisition on the lumbar spine in women with POF, mediated by increased bone formation and decreased bone resorption.

OBJECTIVE

To assess the evolution of body composition and bone metabolism in trans men during the first year of cross-sex hormonal therapy.

METHODS

In a prospective controlled study, we included 23 trans men (female-to-male trans persons) and 23 age-matched control women. In both groups, we examined grip strength (hand dynamometer), biochemical markers of bone turnover (C-terminal telopeptides of type 1 collagen (CTX) and procollagen 1 aminoterminal propeptide (P1NP)), total body fat and lean mass, and areal bone mineral density (aBMD) by dual-X-ray absorptiometry (DXA) and fat and muscle area at the forearm and calf, bone geometry, and volumetric bone mineral density (vBMD) by peripheral quantitative computed tomography (pQCT), before treatment and after 1 year of treatment with undecanoate (1000 mg i.m./12 weeks).

RESULTS

Before hormonal treatment, trans men had similar bone and body composition compared with control women. Testosterone treatment induced in trans men a gain in muscle mass (+10.4%) and strength and loss of fat mass (-9.7%) (all P<0.001) and increased the levels of P1NP and CTX (both P<0.01). Areal and volumetric bone parameters remained largely unchanged apart from a small increase in trabecular vBMD at the distal radius and in BMD at the total hip in trans men (P=0.036 and P=0.001 respectively). None of these changes were observed in the control group.

CONCLUSIONS

Short-term testosterone treatment in trans men increased muscle mass and bone turnover. The latter may rather reflect an anabolic effect of testosterone treatment rather than bone loss.

Pregnancy invokes a doubling of intestinal calcium absorption whereas lactation programs skeletal resorption to provide calcium to milk. Postweaning bone formation restores the skeleton's bone mineral content (BMC), but the factors that regulate this are not established. We used Pth-null mice to test whether parathyroid hormone (PTH) is required for postweaning skeletal recovery. On a normal 1% calcium diet, wild-type (WT) and Pth-null mice each gained BMC during pregnancy, declined 15% to 18% below baseline during lactation, and restored the skeleton above baseline BMC within 14 days postweaning. A 2% calcium diet reduced the lactational decline in BMC without altering the gains achieved during pregnancy and postweaning. The hypocalcemia and hyperphosphatemia of Pth-null mice normalized during lactation and serum calcium remained normal during postweaning. Osteocalcin and propeptide of type 1 collagen (P1NP) each rose significantly after lactation to similar values in WT and Pth-null. Serum calcitriol increased fivefold during pregnancy in both genotypes whereas vitamin D binding protein levels were unchanged. Absence of PTH blocked a normal rise in fibroblast growth factor-23 (FGF23) during pregnancy despite high calcitriol. A 30-fold higher expression of Cyp27b1 in maternal kidneys versus placenta suggests that the pregnancy-related increase in calcitriol comes from the kidneys. Conversely, substantial placental expression of Cyp24a1 may contribute significantly to the metabolism of calcitriol. In conclusion, PTH is not required to upregulate renal expression of Cyp27b1 during pregnancy or to stimulate recovery from loss of BMC caused by lactation. A calcium-rich diet in rodents suppresses skeletal losses during lactation, unlike clinical trials that showed no effect of supplemental calcium on lactational decline in BMC.

Nonpharmacologic approaches to preserve or increase bone mineral density (BMD) include whole-body vibration (WBV), but its efficacy in elderly persons is not clear. Therefore, we conducted the Vibration to Improve Bone in Elderly Subjects (VIBES) trial, a randomized, placebo-controlled trial of 10 minutes of daily WBV (0.3g at 37 Hz) in seniors recruited from 16 independent living communities. The primary outcomes were volumetric BMD of the hip and spine measured by quantitative computed tomography (QCT) and biochemical markers of bone turnover. We randomized 174 men and women (89 active, 85 placebo) with T-scores -1 to -2.5 who were not taking bone active drugs and had no diseases affecting the skeleton (mean age 82 ± 7 years, range 65 to 102). Participants received daily calcium (1000 mg) and vitamin D (800 IU). Study platforms were activated using radio frequency ID cards providing electronic adherence monitoring; placebo platforms resembled the active platforms. In total, 61% of participants in the active arm and 73% in the placebo arm completed 24 months. The primary outcomes, median percent changes (interquartile range [IQR]) in total volumetric femoral trabecular BMD (active group (2.2% [-0.8%, 5.2%]) versus placebo 0.4% [-4.8%, 5.0%]) and in mid-vertebral trabecular BMD of L1 and L2 (active group (5.3% [-6.9%, 13.3%]) versus placebo (2.4% [-4.4%, 11.1%]), did not differ between groups (all p values>> 0.1). Changes in biochemical markers of bone turnover (P1NP and sCTX) also were not different between groups (p = 0.19 and p = 0.97, respectively). In conclusion, this placebo-controlled randomized trial of daily WBV in older adults did not demonstrate evidence of significant beneficial effects on volumetric BMD or bone biomarkers; however, the high variability in vBMD changes limited our power to detect small treatment effects. The beneficial effects of WBV observed in previous studies of younger women may not occur to the same extent in elderly individuals.

During early menopause, steady-state bone remodeling is perturbed; the number of basic multicellular units (BMUs) excavating cavities upon the endosteal surface exceeds the number (generated before menopause) concurrently refilling. Later in menopause, steady-state is restored; the many BMUs generated in early menopause refill as similarly large numbers of BMUs concurrently excavate new cavities. We hypothesized that risedronate reduces the number of cavities excavated. However, in younger postmenopausal women, the fewer cavities excavated will still exceed the fewer BMUs now refilling, so net porosity increases, but less than in controls. In older postmenopausal women, the fewer cavities excavated during treatment will be less than the many (generated during early menopause) now refilling, so net porosity decreases and trabecular volumetric bone mineral density (vBMD) increases. We recruited 324 postmenopausal women in two similarly designed double-blind placebo-controlled studies that included 161 younger (Group 1, ≤ 55 years) and 163 older (Group 2, ≥ 55 years) women randomized 2:1 to risedronate 35 mg/week or placebo. High-resolution peripheral computed tomography was used to image the distal radius and tibia. Cortical porosity was quantified using the StrAx1.0 software. Risedronate reduced serum carboxyterminal cross-linking telopeptide of type 1 bone collagen (CTX-1) and serum amino-terminal propeptide of type 1 procollagen (P1NP) by ∼50%. In the younger group, distal radius compact-appearing cortex porosity increased by 4.2% ± 1.6% (p = 0.01) in controls. This was prevented by risedronate. Trabecular vBMD decreased by 3.6% ± 1.4% (p = 0.02) in controls and decreased by 1.6% ± 0.6% (p = 0.005) in the risedronate-treated group. In the older group, changes did not achieve significance apart from a reduction in compact-appearing cortex porosity in the risedronate-treated group (0.9% ± 0.4%, p = 0.047). No between-group differences reached significance. Results were comparable at the distal tibia. Between-group differences were significant for compact-appearing cortex porosity (p = 0.005). Risedronate slows microstructural deterioration in younger and partly reverses it in older postmenopausal women, features likely to contribute to antifracture efficacy.

BACKGROUND

Animal studies indicate that osteocalcin (OC), particularly the undercarboxylated isoform (unOC), affects insulin sensitivity and secretion, but definitive data from humans are lacking.

OBJECTIVE

The objectives of the study were to determine whether total OC and unOC are independently associated with insulin sensitivity and β-cell response in overweight/obese adults; whether glucose tolerance status affects these associations; and whether the associations are independent of bone formation, as reflected in procollagen type 1 amino propeptide (P1NP).

METHODS

This was a cross-sectional study conducted at a university research center involving 63 overweight/obese adults with normal (n = 39) or impaired fasting glucose (IFG; n = 24).

METHODS

Serum concentrations of total/undercarboxylated OC and P1NP were assessed by RIA; insulin sensitivity was determined by iv glucose tolerance test (S(I)-IVGTT), liquid meal test (S(I) meal), and homeostasis model assessment of insulin resistance; β-cell response to glucose [basal β-cell response to glucose; dynamic β-cell response to glucose; static β-cell response to glucose; and total β-cell response to glucose] was derived using C-peptide modeling of meal test data; and intraabdominal adipose tissue was measured using computed tomography scanning.

RESULTS

Multiple linear regression, adjusting for intraabdominal adipose tissue and P1NP, revealed that total OC was positively associated with S(I)-iv glucose tolerance test (P < .01) in the total sample. OC was not associated with S(I) meal or homeostasis model assessment of insulin resistance. In participants with IFG, unOC was positively associated with static β-cell response to glucose and total β-cell response to glucose (P < .05), independent of insulin sensitivity.

CONCLUSIONS

In overweight/obese individuals, total OC may be associated with skeletal muscle but not hepatic insulin sensitivity. unOC is uniquely associated with β-cell function only in individuals with IFG. Further research is needed to probe the causal inference of these relationships and to determine whether indirect nutrient sensing pathways underlie these associations.

OBJECTIVE

The FACT study (Fosamax Actonel Comparison Trial) was a 1-year-head-to-head trial comparing the efficacy and tolerability of once weekly (DW) alendronate 70 mg and OW risedronate 35 mg for the treatment of postmenopausal osteoporosis. The present analysis was performed to determine the percentage of patients who had changes during the study in BMD and biochemical markers (BCMs) of bone turnover above or below specific cut-off points. A subgroup analysis of upper gastrointestinal (UGI) tolerability was also performed.

METHODS

1053 postmenopausal women with low BMD were randomized to alendronate 70 mg OW (N = 520) or risedronate 35 mg OW (N = 533). The percentage of patients who had measured BMD gains>> or = 3%, and>> or = 5% after 12 months at the hip trochanter, total hip, femoral neck, and lumbar spine (LS) was analyzed. The percentage of patients who experienced any bone loss, and those with measured losses of 3% or more at these sites after 12 months, was determined. The percentage of patients achieving reductions in urinary N-telopeptide of type 1 human collagen (NTX)>> or = 40%, and serum C-telopeptide of type 1 collagen (CTx)>> or = 60%, bone-specific phosphatase (BSAP)>> or = 30%, and N terminal propeptide of type 1 procollagen (P1NP)>> or = 50% at 3 months and 12 months was also determined. Tolerability, based on adverse experience reporting, was evaluated in a subgroup of patients with history of UGI disorders at baseline.

RESULTS

A greater percentage of alendronate- than risedronate-treated patients had measured BMD gains >> or = 0%) (p < 0.05) at all sites at 12 months. Significantly more (p < 0.01) alendronate- than risedronate-treated patients had measured gains in BMD>> or = 3% and>> or = 5% at the hip trochanter, total hip, and LS spine. Significantly more (p < 0.05) risedronate- than alendronate-treated patients had an apparent loss of BMD >> 0% and>> or = 3% loss) at the same sites. After 3 months, significantly (p < 0.001) more alendronate- than risedronate- treated patients achieved predefined reductions in all BCMs. Similar tolerability was demonstrated in both treatment groups, regardless of whether or not patients had a history of UGI disorders at baseline.

CONCLUSIONS

Significantly more alendronate- than risedronate-treated patients achieved predefined increases in BMD at 12 months and reductions in BCMs at 3 months. Significantly more risedronate- than alendronate-treated patients were classified as apparent 'non-responders' (i.e. experienced any bone loss) after 12 months of therapy. The tolerability profiles of the two medications were similar.

The spectrum of therapeutic options and the amount of clinical trials for male osteoporosis (mOP) is lower than those for postmenopausal osteoporosis. Therefore, we examined the effects of 24 months of ibandronate (IBN) treatment (3 mg/3 mL intravenously every 3 months) on bone material quality in 19 subjects with mOP within an open-label, single-center, prospective phase III study (Eudract number 2006-006692-20). Patients (median age [25th, 75th percentiles] 53.0 [44.5; 57.0] years) were included if they had low bone mineral density (BMD) and/or at least one low trauma fracture and no secondary cause of osteoporosis. The primary endpoint was to evaluate IBN effects on cancellous (Cn.) and cortical (Ct.) bone mineralization density distribution (BMDD) based on quantitative backscattered electron imaging (qBEI) of paired transiliacal bone biopsies (baseline, 24 months). Secondary endpoints included changes in areal bone mineral density (BMD by dual-energy X-ray absorptiometry [DXA]) and serum markers of bone turnover including type I collagen peptides CrossLaps (CTX), procollagen type 1 amino-terminal propeptide (P1NP), and osteocalcin (OC). At baseline, cancellous bone matrix mineralization from mOP was lower than published reference data (mean degree of mineralization Cn.CaMean -1.8%, p < 0.01). IBN treatment increased calcium concentrations versus baseline (Cn.CaMean +2.4%, Ct.CaMean, +3.0% both p < 0.01), and reduced heterogeneity of mineralization (Cn.CaWidth -14%, p = 0.044; Ct.CaWidth, -16%, p = 0.001), leading to cancellous BMDD within normal range. IBN treatment was associated with a decrease in porosity of mineralized cortical tissue (-25%, p = 0.01); increases in BMD at the lumbar spine, the femoral neck, and the total hip (+3.3%, +1.9%, and +5.6%, respectively, p ≤ 0.01); and reductions in CTX (-37.5%), P1NP (-44.4%), and OC (-36.3%, all p < 0.01). Our BMDD findings are in line with the reduction of bone turnover markers and the increase in BMD by IBN in our patients and suggest that the latter mainly reflects the increase in matrix mineralization and the reduction of cortical porosity in this cohort with mOP.

Cathepsin K inhibitors (CatK-I) have been developed and established to restore bone mass in both animal models of bone loss and postmenopausal osteoporotic patients. We investigated the effects of a CatK-I L-006235 on bone repair and compared to alendronate (ALN) for its known effects on fracture healing in preclinical models. Femoral fractures were performed on wild type mice that were given vehicle (CON), CatK-I or ALN from day 0 post-fracture until euthanasia. Radiologic and micro-CT analyses demonstrated that CatK-I enhanced mineralization within the calluses at day 21 post-fracture, but to a lesser degree than ALN. Histological analyses showed residual unmineralized and mineralized cartilage in the calluses of CatK-I and ALN treated groups at day 21 post-fracture compared to that in CON. CatK-I enhanced the number of tartrate-resistant acid phosphatase positive (TRAP+) osteoclasts in the fracture calluses compared to ALN and CON treated groups. However, relative levels of serum C-terminal telopeptides of type I collagen (CTX) normalized to the number of TRAP+ osteoclasts within the calluses were significantly decreased in both CatK-I and ALN groups compared to CON. Additionally, the percentages of osteoblast surface over mineralized calluses and levels of the bone formation marker serum N-terminal propeptide of type I procollagen (P1NP) were comparable between CatK-I versus CON groups, while these bone formation parameters were decreased by ALN. Taken together, these results indicate that unlike ALN, CatK-I inhibits osteoclastic activity without changing bone formation, and the inhibition of CatK delayed but did not abrogate callus remodeling during bone repair.

Sclerostin functions as an antagonist to Wnt signaling and inhibits bone-forming activity. We studied the effects of skeletal unloading and treatment with sclerostin antibody (Scl-Ab) on mesenchymal stem cell, osteoprogenitor and osteoclast precursor pools, and their relationship to bone formation and resorption. Male C57BL/6 mice (5-months-old) were hind limb unloaded for 1 week or allowed normal ambulation and treated with Scl-Ab (25 mg/kg, s.c. injections on days 1 and 4) or placebo. Unloading decreased the serum concentration of bone formation marker P1NP (-35 %), number of colony-forming units (CFU) (-38 %), alkaline phosphatase-positive CFUs (CFU-AP+) (-51 %), and calcified nodules (-35 %); and resulted in a fourfold increase in the number of osteoclast precursors. The effects of Scl-Ab treatment on unloaded and normally loaded mice were nearly identical; Scl-Ab increased serum P1NP and the number of CFU, CFU-AP+, and calcified nodules in ex vivo cultures; and increased osteoblast and bone mineralizing surfaces in vivo. Although the marrow-derived osteoclast precursor population increased with Scl-Ab, the bone osteoclast surface did not change, and the serum concentration of osteoclast activity marker TRACP5b decreased. Our data suggest that short-term Scl-Ab treatment can prevent the decrease in osteoprogenitor population associated with skeletal unloading and increase osteoblast surface and bone mineralizing surface in unloaded animals. The anabolic effects of Scl-Ab treatment on bone are preserved during skeletal unloading. These findings suggest that Scl-Ab treatment can both increase bone formation and decrease bone resorption, and provide a new means for prevention and treatment of disuse osteoporosis.

Antidepressants are associated with bone loss and fractures in older adults. We treated depressed older adults with an antidepressant and examined its effects on bone turnover by comparing blood samples before and after treatment. Bone resorption increased after antidepressant treatment, which may increase fracture risk.

BACKGROUND

Antidepressants have been associated with increased bone loss and fractures in older adults in observational studies, but the mechanism is unclear. We examined the effects of a serotonin-norepinephrine reuptake inhibitor, venlafaxine, on biomarkers of bone turnover in a prospective treatment study of late-life depression.

METHODS

Seventy-six individuals aged 60 years and older with current major depressive disorder received a 12-week course of venlafaxine XR 150-300 mg daily. We measured serum C-terminal cross-linking telopeptide of type I collagen (β-CTX) and N-terminal propeptide of type I procollagen (P1NP), measures of bone resorption and formation, respectively, before and after treatment. We then analyzed the change in β-CTX and P1NP within each participant. Venlafaxine levels were measured at the end of the study. We assessed depression severity at baseline and remission status after treatment.

RESULTS

After 12 weeks of venlafaxine, β-CTX increased significantly, whereas P1NP did not significantly change. The increase in β-CTX was significant only in participants whose depression did not remit (increase by 10 % in non-remitters vs. 4 % in remitters). Change in β-CTX was not correlated with serum levels of venlafaxine or norvenlafaxine.

CONCLUSIONS

Our findings suggest that the primary effect of serotonergic antidepressants is to increase bone resorption. However, such an increase in bone resorption seemed to depend on whether or not participants' depression remitted. Our results are in agreement with prior observational studies reporting increased bone loss in older adults taking serotonergic antidepressants. These negative effects on bone homeostasis could potentially contribute to increased fracture risk in older adults.

The acid load accompanying modern diets may have adverse effects on bone and muscle metabolism. Treatment with alkaline salts of potassium can neutralize the acid load, but the optimal amount of alkali is not established. Our objective was to determine the effectiveness of two doses of potassium bicarbonate (KHCO3 ) compared with placebo on biochemical markers of bone turnover, and calcium and nitrogen (N) excretion. In this double-blind, randomized, placebo-controlled study, 244 men and women age 50 years and older were randomized to placebo or 1 mmol/kg or 1.5 mmol/kg of KHCO3 daily for 3 months; 233 completed the study. The primary outcomes were changes in 24-hour urinary N-telopeptide (NTX) and N; changes in these measures were compared across the treatment groups. Exploratory outcomes included 24-hour urinary calcium excretion, serum amino-terminal propeptide of type I procollagen (P1NP), and muscle strength and function assessments. The median administered doses in the low-dose and high-dose groups were 81 mmol/day and 122 mmol/day, respectively. When compared with placebo, urinary NTX declined significantly in the low-dose group (p = 0.012, after adjustment for baseline NTX, gender, and change in urine creatinine) and serum P1NP declined significantly in the low-dose group (p = 0.004, adjusted for baseline P1NP and gender). Urinary calcium declined significantly in both KHCO3 groups versus placebo (p < 0.001, adjusted for baseline urinary calcium, gender, and changes in urine creatinine and calcium intake). There was no significant effect of either dose of KHCO3 on urinary N excretion or on the physical strength and function measures. KHCO3 has favorable effects on bone turnover and calcium excretion and the lower dose appears to be the more effective dose. Long-term trials to assess the effect of alkali on bone mass and fracture risk are needed.

To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analogue, in obese people with hypertriglyceridaemia on atorvastatin, with or without type 2 diabetes.

Participants received PF-05231023 or placebo intravenously once weekly for 4 weeks. Safety (12-lead ECGs, vital signs, adverse events [AEs], laboratory tests) and longitudinal weight assessments were performed. Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Cardiovascular safety studies were also conducted in telemetered rats and monkeys. Blood pressure (BP; mean, systolic and diastolic) and ECGs were monitored.

A total of 107 people were randomized. PF-05231023 significantly decreased mean placebo-adjusted fasting triglycerides (day 25, 33%-43%) and increased HDL cholesterol (day 25, 15.7%-28.6%) and adiponectin (day 25, 1574 to 3272 ng/mL) across all doses, without significant changes in body weight (day 25, -0.45% to -1.21%). Modest decreases from baseline were observed for N-terminal propeptides of type 1 collagen (P1NP) on day 25, although C-telopeptide cross-linking of type 1 collagen (CTX-1) increased minimally. Systolic, diastolic BP, and pulse rate increased in a dose- and time-related manner. There were 5 serious AEs (one treatment-related) and no deaths. Three participants discontinued because of AEs. The majority of AEs were gastrointestinal. PF-05231023 increased BP and heart rate in rats, but not in monkeys.

Once-weekly PF-05231023 lowered triglycerides markedly in the absence of weight loss, with modest changes in markers of bone homeostasis. This is the first report showing increases in BP and pulse rate in humans and rats after pharmacological administration of a long-acting FGF21 molecule.