Profile of changes in bone turnover markers during once-weekly teriparatide administration for 24 weeks in postmenopausal women with osteoporosis

Summary

Changes in bone turnover markers with weekly 56.5 μg teriparatide injections for 24 weeks were investigated in women with osteoporosis. Changes in bone turnover markers 24 h after each injection of teriparatide were constant. During the 24 week period, bone formation markers increased and baseline bone resorption marker levels were maintained.

Introduction

This study aimed to clarify the changes in bone turnover markers during 24 weeks of once-weekly teriparatide injections in postmenopausal women with osteoporosis.

Methods

The 24 h changes in pharmacokinetics (PK), calcium metabolism, and bone turnover markers (serum osteocalcin, procollagen type I N-terminal propeptide (P1NP), urinary cross-linked N-telopeptide of type I collagen (NTX), deoxypiridinoline (DPD)) after each injection of 56.5 μg teriparatide at the data collection weeks (0, 4, 12, and 24 weeks) were investigated. The changes were evaluated by comparison with the data at 0 h in each data collection week.

Results

Similar 24 h changes in each parameter after injection of teriparatide were observed in each data collection week. Serum calcium increased transiently, and intact PTH decreased 4–8 h after injection; serum calcium subsequently returned to baseline levels. Calcium and intact PTH levels decreased for 24 weeks. Although serum osteocalcin decreased at 24 h, it was significantly increased at 4 weeks. P1NP decreased transiently and then increased significantly at 24 h. P1NP was significantly increased at 4 weeks. Urinary NTX and DPD were significantly increased transiently and then decreased at 24 h. The urinary DPD level decreased significantly at 4 weeks.

Conclusions

Twenty-four hour changes in PK, calcium metabolism, and bone turnover markers showed the same direction and level after once-weekly teriparatide injections for 24 weeks, with no attenuation of the effect over time. After 24 weeks, the bone formation marker, serum osteocalcin, increased significantly, but the serum P1NP, did not. Bone resorption markers decreased or remained the same.     

Actions of osteoporosis treatments on bone histomorphometric remodeling: a two-fold principal component analysis

Summary

This was the first study to apply principal component analysis method to bone histomorphometric parameters. The results corroborated teriparatide’s distinct, yet different, mechanisms of action, which stimulate both bone formation and resorption.

Introduction

This study consolidated bone histomorphometric parameters and compared the effects of two osteoporosis treatments on bone remodeling by using a principal component analysis (PCA).

Methods

Included in this analysis were postmenopausal women with osteoporosis who were treated with either teriparatide or alendronate and who completed transiliac bone biopsy at either 6 or 18 months in the randomized, double-blind Forteo Alendronate Comparator Trial. Eighteen histomorphometric parameters were grouped into formation and resorption categories. The first principal component of each category was estimated through the PCA. The summation of principal formation component (PFC) and principal resorption component (PRC) was calculated to represent the overall level of bone turnover. The difference between PFC and PRC was computed to determine the balance between formation and resorption.

Results

The PFC was significantly higher in the teriparatide group than in the alendronate group (P?<?0.0001), while the PRC was numerically lower in the alendronate group (P?=?0.18). The mean difference between the PFC and PRC was positive in the teriparatide group and negative in the alendronate group.

Conclusions

Our approach of consolidating bone histomorphometric remodeling parameters corroborated the idea that the distinct, yet different, mechanisms of action of teriparatide treatment stimulate both bone formation and resorption, and alendronate treatment suppresses both bone formation and resorption.     

The effects of once-weekly teriparatide on hip structure and biomechanical properties assessed by CT

Summary

Once-weekly administration of 56.5 μg teriparatide improved cortical bone parameters and biomechanical parameters at the proximal femur by CT geometry analysis.

Introduction

The aim of this study was to evaluate the effects of weekly administration of teriparatide [human PTH (1–34)] on bone geometry, volumetric bone mineral density (vBMD), and parameters of bone strength at the proximal femur which were longitudinally investigated using computed tomography (CT).

Methods

The subjects were a subgroup of a recent, randomly assigned, double-blind study (578 subjects) comparing the anti-fracture efficacy of a once-weekly subcutaneous injection of 56.5 μg teriparatide with placebo (TOWER trial).

Results

Sixty-six ambulatory postmenopausal women with osteoporosis were enrolled at 15 study sites having multi-detector row CT, and included women injected with teriparatide (n?=?29, 74.2?±?5.1 years) or with placebo (n?=?37, 74.8?±?5.3 years). CT data were obtained at baseline and follow-up scans were performed at 48 and 72 weeks. The data were analyzed to obtain cross-sectional densitometric, geometric, and biomechanical parameters including the section modulus (SM) and buckling ratio (BR) of the femoral neck, inter-trochanter, and femoral shaft. We found that once-weekly teriparatide increased cortical thickness/cross-sectional area (CSA) and total area, and improved biomechanical properties (i.e., decreasing BR) at the femoral neck and shaft. Teriparatide did not change the cortical perimeter.

Conclusions

Our longitudinal analysis of proximal femur geometry by CT revealed that once-weekly administration of 56.5 μg teriparatide improved cortical bone parameters at the femoral neck and shaft and also improved biomechanical parameters.     

Aggravation of spinal cord compromise following new osteoporotic vertebral compression fracture prevented by teriparatide in patients with surgical contraindications

Summary

Patients with spinal cord deficits following new unstable osteoporotic compression fracture and surgical contraindications were considered to receive conservative treatment. Teriparatide was better than alendronate at improving bone mineral density and bone turnover parameters, as well as preventing aggravation of spinal cord compromise.

Introduction

This study compared the preventive effects of teriparatide and alendronate on aggravation of spinal cord compromise following new unstable osteoporotic vertebral compression fracture (OVCF) in patients with surgical contraindications.

Methods

This was a 12-month, randomized, open-label study of teriparatide versus alendronate in 49 patients with new unstable OVCF and surgical contraindications. Neurological function was evaluated using modified Japanese Orthopedic Association (mJOA) score (11-point scale, the maximum score of 11 implies normalcy). Visual analog scale (VAS) scores, kyphotic angles, anterior-border heights and diameters of the spinal canal of the fractured vertebrae, any incident of new OVCFs (onset of OVCF during follow-up), spine bone mineral density (BMD), and serum markers of bone resorption and bone formation were also examined at baseline and 1, 3, 6, and 12 months after initiation of the medication regimen.

Results

At 12 months, mean mJOA score had improved in the teriparatide group and decreased in the alendronate group. Mean concentrations of bone formation and bone resorption biomarkers, mean spine BMD, and mean anterior-border height and spinal canal diameter of the fractured vertebrae were significantly greater in the teriparatide group than in the alendronate group. Mean VAS score, mean kyphotic angle of the fractured vertebrae, and incidence of new OVCFs were significantly smaller in the teriparatide group than in the alendronate group.

Conclusions

In patients with neurological deficits following new unstable OVCF and with surgical contraindications, teriparatide was better than alendronate at improving the BMD and the bone turnover parameters, as well as preventing aggravation of spinal cord compromise.

     

Early changes in biochemical markers of bone turnover and their relationship with bone mineral density changes after 24?months of treatment with teriparatide

Summary

We report the changes in biochemical markers of bone formation during the first 6?months of teriparatide therapy in postmenopausal women with osteoporosis according to previous antiresorptive treatment. Prior therapy does not adversely affect the response to teriparatide treatment. Similar bone markers levels are reached after 6?months of treatment.

Introduction

The response of biochemical markers of bone turnover with teriparatide therapy in subjects who have previously received osteoporosis drugs is not fully elucidated. We examined biochemical markers of bone formation in women with osteoporosis treated with teriparatide and determined: (1) whether the response is associated with prior osteoporosis therapy, (2) which marker shows the best performance for detecting a response to therapy, and (3) the correlations between early changes in bone markers and subsequent bone mineral density (BMD) changes after 24?months of teriparatide.

Methods

We conducted a prospective, open-label, 24-month study at 95 centers in 10 countries in 758 postmenopausal women with established osteoporosis (n?=?181 treatment-na?ve) who had at least one post-baseline bone marker determination. Teriparatide (20 ??g/day) was administered for up to 24?months. We measured procollagen type I N-terminal propeptide (PINP), bone-specific alkaline phosphatase (b-ALP), and total alkaline phosphatase (t-ALP) at baseline, 1 and 6?months, and change in BMD at the lumbar spine, total hip and femoral neck from baseline to 24?months.

Results

Significant increases in formation markers occurred after 1?month of teriparatide regardless of prior osteoporosis therapy. The absolute increase at 1?month was lower in previously treated versus treatment-na?ve patients, but after 6?months all groups reached similar levels. PINP showed the best signal-to-noise ratio. Baseline PINP correlated positively and significantly with BMD response at 24?months.

Conclusions

This study suggests that the long-term responsiveness of bone formation markers to teriparatide is not affected in subjects previously treated with antiresorptive drugs.     

Comparative effects of teriparatide and ibandronate on spine bone mineral density (BMD) and microarchitecture (TBS) in postmenopausal women with osteoporosis: a 2-year open-label study

Summary

Treatment effects over 2 years of teriparatide vs. ibandronate in postmenopausal women with osteoporosis were compared using lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). Teriparatide induced larger increases in BMD and TBS compared to ibandronate, suggesting a more pronounced effect on bone microarchitecture of the bone anabolic drug.

Introduction

The trabecular bone score (TBS) is an index of bone microarchitecture, independent of bone mineral density (BMD), calculated from anteroposterior spine dual X-ray absorptiometry (DXA) scans. The potential role of TBS for monitoring treatment response with bone-active substances is not established. The aim of this study was to compare the effects of recombinant human 1–34 parathyroid hormone (teriparatide) and the bisphosphonate ibandronate (IBN), on lumbar spine (LS) BMD and TBS in postmenopausal women with osteoporosis.

Methods

Two patient groups with matched age, body mass index (BMI), and baseline LS BMD, treated with either daily subcutaneous teriparatide (N?=?65) or quarterly intravenous IBN (N?=?122) during 2 years and with available LS BMD measurements at baseline and 2 years after treatment initiation were compared.

Results

Baseline characteristics (overall mean ± SD) were similar between groups in terms of age 67.9?±?7.4 years, body mass index 23.8?±?3.8 kg/m², BMD L1–L4 0.741?±?0.100 g/cm², and TBS 1.208?±?0.100. Over 24 months, teriparatide induced a significantly larger increase in LS BMD and TBS than IBN (+7.6 %?±?6.3 vs. +2.9 %?±?3.3 and +4.3 %?±?6.6 vs. +0.3 %?±?4.1, respectively; P?<?0.0001 for both). LS BMD and TBS were only weakly correlated at baseline (r ²?=?0.04) with no correlation between the changes in BMD and TBS over 24 months.

Conclusions

In postmenopausal women with osteoporosis, a 2-year treatment with teriparatide led to a significantly larger increase in LS BMD and TBS than IBN, suggesting that teriparatide had more pronounced effects on bone microarchitecture than IBN.     

Preventive effects of conservative treatment with short-term teriparatide on the progression of vertebral body collapse after osteoporotic vertebral compression fracture

Summary

The progression of fractured vertebral collapse is not rare after a conservative treatment of vertebral compression fracture (VCF). Teriparatide has been shown to directly stimulate bone formation and improve bone density, but there is a lack of evidence regarding its use in fracture management. Conservative treatment with short-term teriparatide is effective for decreasing the progression of fractured vertebral body collapse.

Introduction

Few studies have reported on the prevention of collapsed vertebral body progression after osteoporotic VCF. Teriparatide rapidly enhances bone formation and increases bone strength. This study evaluated preventive effects of short-term teriparatide on the progression of vertebral body collapse after osteoporotic VCF.

Methods

Radiographs of 68 women with single-level osteoporotic VCF at thoracolumbar junction (T11–L2) were reviewed. Among them, 32 patients were treated conservatively with teriparatide (minimum 3 months) (group I), and 36 were treated with antiresorptive (group II). We measured kyphosis and wedge angle of the fractured vertebral body, and ratios of anterior, middle, and posterior heights of the collapsed body to posterior height of a normal upper vertebra were determined. The degree of collapse progression was compared between two groups.

Results

The progression of fractured vertebral body collapse was shown in both groups, but the degree of progression was significantly lower in group I than in group II. At the last follow-up, mean increments of kyphosis and wedge angle were significantly lower in group I (4.0°?±?4.2° and 3.6°?±?3.6°) than in group II (6.8°?±?4.1° and 5.8°?±?3.5°) (p?=?0.032 and p?=?0.037). Decrement percentages of anterior and middle border height were significantly lower in group I (9.6?±?10.3 and 7.4?±?7.5 %) than in group II (18.1?±?9.7 and 13.8?±?12.2 %) (p?=?0.001 and p?=?0.025), but not in posterior height (p?=?0.086).

Conclusions

In female patients with single-level osteoporotic VCF at the thoracolumbar junction, short-term teriparatide treatment did not prevent but did decrease the progression of fractured vertebral body collapse.     

Comparison of the effect of 18-month daily teriparatide administration on patients with rheumatoid arthritis and postmenopausal osteoporosis patients

Summary

Patients with rheumatoid arthritis showed greater response to 18-month administration of daily teriparatide especially in the increase of bone formation markers at 1 month and femoral neck bone mineral density at 18 months compared to postmenopausal osteoporosis patients.

Introduction

The aim of this study was to evaluate the effects of 18-month administration of daily teriparatide (TPTD) in osteoporosis patients with rheumatoid arthritis (RA) by comparing that of postmenopausal osteoporosis patients (Porosis).

Methods

The effects of TPTD were examined between RA (n?=?70; age 68.4 years; disease activity score assessing 28 joints with CRP [DAS28-CRP] 2.8; rheumatoid factor [RF] positivity 75.5 %) with 77.1 % of prior bisphosphonate (BP), 84.3 % of oral prednisolone (PSL) (4.4 mg/day at baseline), 25.7 % of biologics, and Porosis (n?=?62; age 71.3 years) with 77.4 % of prior BP.

Results

Femoral neck (FN) bone mineral density (BMD) increase at 18 months was significantly greater in RA compared to Porosis (4.7 vs. 0.7 %, P?=?0.038), whereas it was 9.7 versus 7.9 % (P?=?0.736) in the lumbar spine (LS). The increase of bone formation markers (bone alkaline phosphatase [bone ALP] and N-terminal type I procollagen propeptide [PINP]) at 1 month were all significantly greater in RA compared to Porosis. A multivariate logistic regression analysis revealed that the significant indicator of 18-month BMD increase in RA was a 3-month increase of under-carboxylated osteocalcin (ucOC) for LS (β?=?0.446, P?=?0.005) and baseline ucOC for FN (β?=?0.554, P?=?0.001), in which both showed significant negative correlation with baseline PSL dose.

Conclusions

RA showed greater response to daily TPTD administration, especially in the increase of bone formation markers at 1 month and FN BMD increase at 18 months compared to Porosis.     

Validation of urinary calcium isotope excretion from bone for screening anabolic therapies for osteoporosis

Summary

Urinary excretion of calcium tracers in labeled individuals decreases in response to antiresorptive therapy, providing a tool to rapidly screen potential therapies. Using teriparatide, we demonstrate in this study that anabolic therapy also decreases tracer excretion, confirming that this method can also be used to screen potential anabolic therapies.

Introduction

Changes in urinary excretion of calcium tracers from a labeled skeleton may be a rapid and sensitive method to screen potential therapies for osteoporosis. This method has been used to screen antiresorptive therapies, but the effect of anabolic therapies on tracer excretion is unknown.

Methods

Eight-month-old female Sprague Dawley rats (n?=?11) were given 50 μCi ⁴⁵Ca iv. After a 1-month equilibration period, baseline urinary ⁴⁵Ca excretion and total bone mineral content (BMC) were measured. Rats were then treated with 30 μg/kg teriparatide sc per day, a bone anabolic agent, for 80 days. Urine was collected throughout the study and analyzed for ⁴⁵Ca and total Ca, and BMC was measured at the beginning and end of the study.

Results

Teriparatide decreased urinary ⁴⁵Ca excretion by 52.1 % and increased BMC by 21.7 %. The change in bone calcium retention as determined by the ratio of ⁴⁵Ca to total Ca excretion in urine from day 6 through 15 of teriparatide treatment was significantly correlated (p?=?0.036) with the change in BMC after 80 days of teriparatide treatment.

Conclusion

Urinary excretion of calcium tracers from labeled bone is an effective method to rapidly screen potential anabolic therapies for osteoporosis.     

Serotonin–norepinephrine reuptake inhibitor therapy in late-life depression is associated with increased marker of bone resorption

Summary

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.

Introduction

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.

Conclusion

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.     

Early changes in biochemical markers of bone formation during teriparatide therapy correlate with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis

Summary

Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide.

Introduction

To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO.

Methods

A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 μg/day, n?=?45) and risedronate (35 mg/week, n?=?47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables.

Results

PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group.

Conclusions

Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.     

Low bone turnover and low bone density in a cohort of adults with Down syndrome

Summary

Increased incidence of osteoporosis in Down syndrome has been reported, but etiology is not established. We report low bone turnover markers and bone mineral density (BMD) in a cohort of people with Down syndrome without consistent clinical risk factors. Our results should guide future studies and treatments for this common problem.

Introduction

To better understand the etiology for osteoporosis in Down syndrome (DS), we measured bone density by dual-energy X-ray absorptiometry (DXA) and circulating biochemical markers of bone formation and resorption in a cohort of 30 community-dwelling DS adults.

Methods

Seventeen males and 13 females followed in the University of Arkansas Down Syndrome Clinic were evaluated by DXA to estimate BMD and underwent phlebotomy to measure serum procollagen type-1 intact N-terminal propeptide (P1NP) to evaluate bone formation, and serum C-terminal peptide of type-I collagen (CTx) to evaluate bone resorption.

Results

Seven of 13 DS females and 12 of 17 DS males had low bone mass at one of measured sites (z?≤??2.0). When data were grouped by age, males had apparent osteopenia earlier than females. The mean P1NP in the normal group was 19.2?±?5.2 ng/ml vs. 2.2?±?0.9 ng/ml in the DS group (P?=?0.002). Serum CTx levels in the normal group were 0.4?±?0.1 ng/ml vs. 0.3?±?0.1 ng/ml (P?=?0.369).

Conclusions

Low BMD in adults with DS is correlated with a significant decrease in bone formation markers, compared to controls without DS, and is independent of gender. These data suggest that diminished osteoblastic bone formation and inadequate accrual of bone mass, with no significant differences in bone resorption, are responsible for the low bone mass in DS. These observations question the use of antiresorptive therapy in this population and focus attention on increasing bone mass by other interventions.     

Teriparatide for osteoporosis: importance of the full course

Teriparatide (TPTD) is the only currently available therapeutic agent that increases the formation of new bone tissue and can provide some remediation of the architectural defects in the osteoporotic skeleton. The use of teriparatide clinically is limited to 24 months. We review clinical findings during daily teriparatide treatment over time. Teriparatide appears to increase bone formation more than bone resorption as determined biochemically and histologically. Teriparatide exerts its positive effects on bone formation in two distinct fashions. The first is direct stimulation of bone formation that occurs within active remodeling sites (remodeling-based bone formation) and on surfaces of bone previously inactive (modeling-based bone formation). The second is an increase in the initiation of new remodeling sites. Both processes contribute to the final increase in bone density observed by non-invasive tools such as DXA. Remodeling is the repair process by which skeletal tissue is maintained in a young healthy state, and when stimulated by TPTD is associated with a positive bone balance within each remodeling cavity. It seems likely therefore that this component will contribute to the anti-fracture efficacy of TPTD. Teriparatide reduces the risk of fracture, and this effect appears to increase with longer duration of therapy. The use of novel treatment regimens, including shorter courses, should be held in abeyance until controlled clinical trials are completed to define the relative fracture benefits of such approaches in comparison to the 24-month daily use of the agent. Summary In patients with osteoporosis at high risk for fracture, the full continuous 24-month course with teriparatide results in improved skeletal health and outcomes than shorter time periods.     

Comparison of treatment effects of teriparatide and the bisphosphonate risedronate in an aged,osteopenic, ovariectomized rat model under various clinical conditions

Teriparatide and bisphosphonates are osteoporosis medications that increase bone mineral density (BMD) and prevent fracture, but each has a different mechanism of action. Teriparatide promotes bone formation, while bisphosphonates suppress bone resorption. In the clinical setting, however, drug selection is not always tailored to the particular clinical condition of the patient or mechanism of action of the drug. We compared the effects of teriparatide and the bisphosphonate risedronate on bone metabolism using two ovariectomized rat models to elucidate the optimal use of these two drugs in the clinical setting. We first performed dose-finding experiments to determine the equivalent effective doses of each drug (5.6 and 3.0 µg/kg for teriparatide and risedronate, respectively). We then compared the effects of these doses on bone metabolism after subcutaneous administration three times weekly for 4 months starting either the day after ovariectomy (preventive study) or 12 months after ovariectomy (therapeutic study). The increase in proximal tibial BMD under the physical conditions that increased bone turnover at 1 to 2 months after ovariectomy was greater in the risedronate group than in the teriparatide group. In contrast, the increases in lumbar vertebral BMD and bone strength under the physical conditions that significantly decreased BMD and bone strength at 12 months after ovariectomy were greater in the teriparatide group than in the risedronate group. The present study provides important information on the selection of antiosteoporotic drugs, including teriparatide and risedronate, in treatment protocols tailored to the clinical conditions of patients and drug mechanisms.     

An algorithm using the early changes in PINP to predict the future BMD response for patients treated with daily teriparatide

Summary

About two thirds of patients with a procollagen type I N-terminal propeptide (PINP) increase of >80 μg/l at 1 month after starting teriparatide therapy showed a ≥10 % increase in lumbar spine (LS) bone mineral density (BMD) from baseline at 12 months. We recommend this algorithm as an aid in the clinical management of patients treated with daily teriparatide.

Introduction

An algorithm using PINP is provided in osteoporotic patients with teriparatide treatment. The correlations between the early changes in PINP and the subsequent BMD changes after daily teriparatide therapy were studied to develop an algorithm to monitor patients.

Methods

We evaluated whether early changes in PINP correlated with the changes in BMD at 12 months and developed an algorithm using the early changes in PINP to predict the upcoming BMD increases.

Results

The highest correlation coefficient for the relationship between PINP and LS BMD response was determined for the absolute change in PINP at 1 month and the percent change in LS BMD at 12 months (r?=?0.36, p <0.01). Using a receiver operator curve analysis, we determined that an 80 μg/l increase in PINP was the most convenient predictor of a 10 % increase in LS BMD from baseline (area under curve?=?0.72). Using a cut-off value of 80 μg/l, the positive predictive value for predicting a 10 % increase in LS BMD from baseline to 12 months was 65 %.

Conclusion

Greater short-term changes in PINP with teriparatide therapy are associated with greater 12-month increases in LS BMD. About two thirds of patients with a PINP increase of >80 μg/l at 1 month after starting treatment showed a ≥10 % increase in LS BMD from baseline at 12 months. We recommend this algorithm as an aid in the clinical management of patients treated with teriparatide.     

Effects of low intensity vibration on bone and muscle in rats with spinal cord injury

Summary

Spinal cord injury (SCI) causes rapid and marked bone loss. The present study demonstrates that low-intensity vibration (LIV) improves selected biomarkers of bone turnover and gene expression and reduces osteoclastogenesis, suggesting that LIV may be expected to benefit to bone mass, resorption, and formation after SCI.

Introduction

Sublesional bone is rapidly and extensively lost following spinal cord injury (SCI). Low-intensity vibration (LIV) has been suggested to reduce loss of bone in children with disabilities and osteoporotic women, but its efficacy in SCI-related bone loss has not been tested. The purpose of this study was to characterize effects of LIV on bone and bone cells in an animal model of SCI.

Methods

The effects of LIV initiated 28 days after SCI and provided for 15 min twice daily 5 days each week for 35 days were examined in female rats with moderate severity contusion injury of the mid-thoracic spinal cord.

Results

Bone mineral density (BMD) of the distal femur and proximal tibia declined by 5 % and was not altered by LIV. Serum osteocalcin was reduced after SCI by 20 % and was increased by LIV to a level similar to that of control animals. The osteoclastogenic potential of bone marrow precursors was increased after SCI by twofold and associated with 30 % elevation in serum CTX. LIV reduced the osteoclastogenic potential of marrow precursors by 70 % but did not alter serum CTX. LIV completely reversed the twofold elevation in messenger RNA (mRNA) levels for SOST and the 40 % reduction in Runx2 mRNA in bone marrow stromal cells resulting from SCI.

Conclusion

The findings demonstrate an ability of LIV to improve selected biomarkers of bone turnover and gene expression and to reduce osteoclastogenesis. The study indicates a possibility that LIV initiated earlier after SCI and/or continued for a longer duration would increase bone mass.     

Efficacy of osteoporosis pharmacotherapies in preventing fracture among oral glucocorticoid users: a network meta-analysis

Summary

Efficacy of osteoporosis medication is not well-established among patients taking oral glucocorticoids. We assessed the efficacy of approved osteoporosis pharmacotherapies in preventing fracture by combining data from randomized controlled trials. Teriparatide, risedronate, and etidronate were associated with decreased vertebral fracture risk.

Introduction

Several osteoporosis drugs are approved for the prevention and treatment of glucocorticoid (GC)-induced osteoporosis. However, the efficacy of these treatments among oral GC users is still limited. We aimed to examine the comparative efficacy of osteoporosis treatments among oral GC users.

Methods

We updated a systematic review through to March 2015 to identify all double-blinded randomized controlled trials (RCTs) that examined osteoporosis treatment among oral GC users. We used a network meta-analysis with informative priors to derive comparative risk ratios (RRs) and 95 % credible intervals (95 % CrI) for vertebral and non-vertebral fracture and mean differences in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD). Treatment ranking was estimated using the surface under the cumulative ranking curve (SUCRA) statistic. A meta-regression was completed to assess a subgroup effect between patients with prior GC exposures and GC initiators.

Results

We identified 27 eligible RCTs examining nine active comparators. Etidronate (RR, 0.41; 95%CrI?=?0.17–0.90), risedronate (RR?=?0.30, 95%CrI?=?0.14–0.61), and teriparatide (RR?=?0.07, 95%CrI?=?0.001–0.48) showed greater efficacy than placebo in preventing vertebral fractures; yet, no treatment effects were statistically significant in reducing non-vertebral fractures. Alendronate, risedronate, and etidronate increased LS BMD while alendronate and raloxifene increased FN BMD. In preventing vertebral fractures, teriparatide was ranked as the best treatment (SUCRA: 77 %), followed by risedronate (77 %) and zoledronic acid (76 %). For non-vertebral fractures, teriparatide also had the highest SUCRA (69 %), followed by risedronate (64 %). No subgroup effect was identified with regards to prior GC exposure.

Conclusions

Despite weak trial evidence available for fracture prevention among GC users, we identified several drugs that are likely to prevent osteoporotic fracture. Teriparatide, risedronate, and etidronate were associated with decreased vertebral fracture risk.

     

Effect of the cathepsin K inhibitor odanacatib administered once weekly on bone mineral density in Japanese patients with osteoporosis—a double-blind, randomized, dose-finding study

Summary

The efficacy and safety of oral placebo or odanacatib 10, 25, or 50 mg once weekly for 52 weeks were evaluated in a double-blind, randomized, multi-center study in Japanese female and male patients with osteoporosis.

Introduction

Odanacatib is a selective and reversible cathepsin K inhibitor that decreases bone resorption and increases bone mineral density (BMD).

Methods

The primary efficacy endpoint was percent change from baseline to week 52 in lumbar spine BMD. Secondary endpoints included percent change in total hip, femoral neck, and trochanter BMD and in bone biomarkers after treatment for 52 weeks.

Results

In this study, 286 patients [94 % female, mean age (SD) 68.2 (7.1) years] were included in the analysis. The least-squares mean percent changes from baseline to week 52 in the groups receiving placebo, 10, 25 and 50 mg of odanacatib for lumbar spine (L1～L4) BMD were 0.5, 4.1, 5.7, and 5.9 % and for total hip BMD were ?0.4, 1.3, 1.8, and 2.7 %, respectively. The changes in femoral neck and trochanter BMD were similar to those at the total hip. Bone turnover markers were reduced in a dose-dependent manner. However, the effects of odanacatib on bone formation markers were less compared with the effects on bone resorption markers. Tolerability and safety profiles were similar among all treatment groups with no dose-related trends in any adverse events.

Conclusions

Weekly odanacatib treatment for 52 weeks increased BMD at the lumbar spine and at all hip sites in a dose-dependent manner and was well tolerated in Japanese patients with osteoporosis.     

Histomorphometric changes by teriparatide in alendronate-pretreated women with osteoporosis

Summary

The level of increased bone formation after 24 months of treatment with teriparatide (rhPTH (1–34), TPTD) is similar in patients who were either treatment-naïve (TN) or had lower bone turnover initially due to previous alendronate (ALN) therapy.

Introduction

Bone anabolic effects of TPTD in postmenopausal women with osteoporosis may be blunted during the initial phase after switching from ALN to TPTD. To explore the long-term implications, we examined histomorphometric and biochemical markers of bone turnover of patients on TPTD therapy after long-term ALN treatment.

Methods

Paired biopsies were obtained after tetracycline double labeling at baseline and after 24 months of TPTD treatment from 29 ALN-pretreated (64.5?±?16.4 months) and 16 TN patients. Biochemical markers were measured at baseline, during the treatment, or at study end.

Results

Compared with the baseline, after 24-month TPTD, activation frequency (Ac.F.) and osteoid surface (OS) increased in both groups: 0.11–0.34 cycles per year, 3.96–9.8% in the ALN-pretreated group and 0.19–0.33 cycles per year, 6.2–11.3% (p?<?0.05) in the TN group, respectively. Biochemical and histomorphometric markers correlated positively both at baseline and endpoint. Serum amino terminal propeptide of type I procollagen (PINP) correlated with Ac.F. (r?=?0.57, p?<?0.001 and r?=?0.48, p?<?0.01) and OS (r?=?0.51, p?<?0.01 and r?=?0.56, p?<?0.01) at baseline and endpoint, respectively. Following 3 months of treatment, increases in biochemical markers like PINP predicted the increase in Ac.F. (r?=?0.52, p?<?0.01) and OS (r?=?0.54, p?<?0.01) after 24 months.

Conclusions

The increased level of formation is similar in patients who were either TN or had lower bone turnover initially due to previous ALN therapy. Elevated bone formation in postmenopausal women with osteoporosis was sustained over a 24-month period by TPTD. Biochemical markers of bone formation are a good surrogate for the assessment of TPTD effects.     

Study of the mechanisms by which Sambucus williamsii HANCE extract exert protective effects against ovariectomy-induced osteoporosis in vivo

Summary

The purpose of this study is to investigate the dose-dependent effects of SWH on bone properties and the mechanism involved in mediating the osteoprotective actions of SWH. The results indicated that SWH could improve bone properties by inhibiting the process of bone resorption and stimulating the process of bone formation.

Introduction

Our previous study showed that Sambucus williamsii HANCE (SWH) improved trabecular bone mass and cortical bone strength in ovariectomized (OVX) rats. The purpose of this study is to investigate the dose-dependent effects of SWH on bone properties and the mechanism involved in mediating the osteoprotective actions of SWH.

Methods

Three-month-old C57BL/6J mice were fed a phytoestrogen-free diet and subjected to either ovariectomy or sham operation. OVX mice were treated with genistein (50 mg/kg), or a low (200 mg/kg), medium (500 mg/kg), or high (1,000 mg/kg) dose of SWH extract.

Results

SWH could dose-dependently decrease urinary Ca excretion and increase serum Ca level in OVX mice. It could increase tibial bone mineral density and exert beneficial effects on the microarchitecture of trabecular bone in the OVX mice. SWH suppressed the ovariectomy-induced expression of Cbfa1 mRNA and cathepsin K mRNA and enhanced the ratio of OPG/RANKL mRNA expression in the tibia. In vitro study showed that SWH dramatically reduced the number of TRAP-positive cells in RANKL-induced RAW 264.7 cells.

Conclusions

The present study indicated that SWH could improve bone properties by inhibiting the process of bone resorption and stimulating the process of bone formation.