Peiqi Chen

Change in Lumbar Spine BMD and Vertebral Fracture Risk Reduction in Teriparatide-Treated Postmenopausal Women With Osteoporosis†

Increases in lumbar spine BMD account for 30–41% of the vertebral fracture risk reduction with teriparatide treatment. The remaining fracture risk reduction is caused by improvements in non‐BMD determinants of bone strength.

Severity of vertebral fracture reflects deterioration of bone microarchitecture

IntroductionBone microarchitecture, a component of bone strength, is generally measured on transiliac bone biopsy samples. The objective of this study was to determine whether assessment of four grades of vertebral fracture severity could serve as a noninvasive surrogate marker for trabecular bone volume and microarchitecture.MethodsBaseline vertebral fracture severity was determined by semiquantitative assessment of spine radiographs from 190 postmenopausal women with osteoporosis. Bone-structure indices were obtained by 2D histomorphometry and 3D microcomputed tomography (CT) analyses. Significance of differences was determined after adjusting for age, height, and lumbar spine bone mineral density.ResultsThere were significant (P < 0.05) trends in decreasing bone volume, trabecular number, and connectivity, and increasing trabecular separation with greater vertebral fracture severity. Histomorphometric bone volume was 25 and 36% lower (P < 0.05) in women with moderate and severe fractures than in women with no fractures, respectively. Compared with women without fractures, women with mild, moderate, and severe fractures had lower (P < 0.05) microCT bone volume (23, 30, and 51%, respectively).ConclusionsMicroarchitectural deterioration was progressively worse in women with increasing severity of vertebral fractures. We conclude that assessment of vertebral fracture severity is an important clinical tool to evaluate the severity of postmenopausal osteoporosis.

Development of an algorithm for using PINP to monitor treatment of patients with teriparatide.

ABSTRACT Introduction: Teriparatide effects are mediated via the preferential stimulation of osteoblastic activity over osteoclastic activity. Amino-terminal propeptide of type I procollagen (PINP) is an indicator of osteoblastic activity. Objective: Develop an algorithm using PINP as an aid in the management of patients with postmenopausal osteoporosis treated with teriparatide. Research design and methods: For inclusion in this post-hoc analysis, trials had to be investigations of teriparatide 20 µg/day in postmenopausal women with osteoporosis having measurements of PINP at 3 months and bone mineral density (BMD) at 12 months. Signal-to-noise ratio was calculated for a series of markers of bone turnover in the Fracture Prevention Trial. An algorithm was developed to monitor patients treated with teriparatide using PINP. Results: Three trials met inclusion criteria and included the Fracture Prevention, Forteo-Alendronate Comparator and Anabolic After Antiresorptive trials. PINP had the highest signal-to-noise ratio of all bone-turnover markers. Positive PINP responses defined as increases > 10 µg/L were observed in 77–97% of teriparatide- and in 6% of placebo-treated patients after 3 months of study drug. Mean lumbar spine BMD increases after 12 months of teriparatide in patients having PINP changes > 10 µg/L ranged from 8.3% to 9.5% and in patients with PINP changes ≤ 10 µg/L ranged from 5.9% to 7.6%. In the algorithm, PINP is measured at baseline and after 1–3 months of therapy. Patients with PINP increases > 10 µg/L are given a positive message. Patients with PINP increases ≤ 10 µg/L are assessed for adherence, teriparatide administration and storage techniques, and for the presence of medical conditions that might limit their therapeutic response, and these issues are addressed as appropriate. Patients without these issues and with PINP increases ≤ 10 µg/L should be given a neutral message because BMD may significantly increase with continued therapy. Conclusions: The PINP algorithm provides information regarding the anabolic response to teriparatide therapy and has the potential to identify patients requiring help with issues of adherence, injection technique, teriparatide storage, and medical problems limiting therapeutic responsiveness to teriparatide treatment. Data assessing the relationship of changes in PINP to fracture risk reduction are not available. We recommend physicians audit the use of the algorithm in practice so that improvements can be made.

PINP as an aid for monitoring patients treated with teriparatide

Biochemical markers of bone turnover may be useful aids for managing patients with osteoporosis. A 12-month, phase 3, multicenter trial of Japanese patients at high risk of fracture was conducted to assess the effects of teriparatide 20 μg/day on BMD, serum markers of bone turnover, and safety. Two-hundred and seven subjects (93% female; median age 70 years) were randomized in double-blind fashion 2:1 to teriparatide versus placebo. Bone turnover markers including procollagen type I N-terminal propeptide (PINP), bone-specific alkaline phosphatase (bone ALP) and type I collagen cross-linked C-telopeptide (CTX) were collected at baseline, 1, 3, 6, and 12 months. Lumbar spine, femoral neck, and total hip BMD were measured at baseline, 3, 6, and 12 months. Increases in PINP at 1 month correlated best with increases in lumbar spine BMD at 12 months (r=0.76; P<0.01). The proportions of patients with an increase from baseline in PINP >10 μg/L at 1, 3, and 6 months were 3%, 0%, and 2% in the placebo, and 93%, 87%, and 83% in the teriparatide group. The proportions of patients with an increase in PINP >10 μg/L at either 1 or 3 months were 3% in the placebo and 95% in the teriparatide group (P<0.001). The proportions of patients with a significant increase in lumbar spine BMD (increase from baseline ≥3%) at 12 months were 20% in the placebo and 94% in the teriparatide group. The proportions of patients with an increase in PINP >10 μg/L at 1 or 3 months and an increase in lumbar spine BMD ≥3% at 12 months was 0% of placebo group patients and 92% of teriparatide group patients (P<0.001). These data confirm a strong relationship between early change in PINP and later change in lumbar spine BMD during teriparatide therapy. Also, these results suggest that monitoring with PINP and lumbar spine BMD successfully identifies positive responses in most patients taking teriparatide and negative responses in most patients not taking teriparatide. PINP monitoring may be a useful aid in the management of patients with osteoporosis during teriparatide treatment.

Vertebral fracture status and the world health organization risk factors for predicting osteoporotic fracture risk.

Vertebral fractures are the most common osteoporotic fracture, and patients with prevalent vertebral fractures have a greater risk of future fractures. However, radiographically determined vertebral fractures are not identified as a distinct risk factor in the World Health Organization (WHO) fracture risk assessment tool. The objective of this study was to evaluate and compare potential risk factors including morphometric spine fracture status and the WHO risk factors for predicting 5‐yr fracture risk. We hypothesized that spine fracture status provides prognostic information in addition to consideration of the WHO risk factors alone. A randomly selected, population‐based community cohort of 2761 noninstitutionalized men and women ≥50 yr of age living within 50 km of one of nine regional centers was enrolled in the Canadian Multicentre Osteoporosis Study (CaMOS), a prospective and longitudinal cohort study following subjects for 5 yr. Prevalent and incident spine fractures were identified from lateral spine radiographs. Incident nonvertebral fragility fractures were determined by an annual, mailed fracture questionnaire with validation, and nonvertebral fragility fracture was defined by investigators as a fracture with minimal trauma. A model considering the WHO risk factors plus spine fracture status provided greater prognostic information regarding future fracture risk than a model considering the WHO risk factors alone. In univariate analyses, age, BMD, and spine fracture status had the highest gradient of risk. A model considering these three risk factors captured almost all of the predictive information provided by a model considering spine fracture status plus the WHO risk factors and provided greater predictive information than a model considering the WHO risk factors alone. The use of spine fracture status along with age and BMD predicted future fracture risk with greater simplicity and higher prognostic accuracy than consideration of the risk factors included in the WHO tool.

Teriparatide vertebral fracture risk reduction determined by quantitative and qualitative radiographic assessment.

ABSTRACT Objective: Most registration studies for new osteoporosis drugs have used a combination of quantitative morphometry (QM) and visual semiquantitative reading (SQ) to define vertebral fractures. However, in the pivotal teriparatide Fracture Prevention Trial (ClinicalTrials.gov Identifier: NCT00670501), vertebral fractures were previously defined only by the SQ methodology. The objective of this study was to define the effect of teriparatide on the incidence of vertebral fractures defined by QM plus SQ assessment. Research design and methods: Radiographs from the Fracture Prevention Trial placebo- and teriparatide 20 μg/day groups were re-assessed in blinded fashion, defining incident vertebral fractures for vertebrae meeting all of the following requirements: (a) 20% decrease in height by QM, (b) a corresponding 4 mm decrease in height (c) an increase of at least one grade by visual SQ assessment by a radiologist. Results: By this methodology, vertebral fracture risk was reduced in the teriparatide versus placebo group by 84% (RR = 0.16, p < 0.001). The risk of two or more vertebral fractures was also significantly reduced by 94% (RR = 0.06, p < 0.001). The fractures in the teriparatide group were of lesser severity than the fractures in the placebo group. The absolute benefit of teriparatide was greatest in those patients with the highest number and severity of prevalent vertebral fractures. Conclusions: As assessed by QM plus SQ, teriparatide reduced the incidence of vertebral fractures. Trial registration: ClinicalTrials.gov identifier: NCT00670501.

Correlations between biochemical markers of bone turnover and bone density responses in patients with glucocorticoid-induced osteoporosis treated with teriparatide or alendronate

The purpose of this post hoc analysis was to determine whether baseline concentrations or early changes in serum bone turnover markers were correlated with changes in bone mineral density (BMD) at 18 months in patients with glucocorticoid-induced osteoporosis (GIO) treated with teriparatide (n=80; 20 mug/day) or alendronate (n=77; 10 mg/day). Bone markers included type I collagen N-terminal propeptide (PINP), type I collagen C-terminal propeptide (PICP), bone alkaline phosphatase (bone ALP), and cross-linked C-telopeptide of type I collagen (Sbeta-CTX). The relationship between baseline and early changes in markers and the 18-month changes in lumbar spine (LS) and femoral neck (FN) BMD was evaluated using Spearman correlation analysis. In the teriparatide group, increases in LS and FN BMD at 18 months were not significantly correlated with baseline marker concentrations (P>0.05) but were correlated with the increases in PINP at 1 and 6 months (P<0.05). In the alendronate group, the increase in FN BMD at 18 months was positively correlated with baseline marker concentrations (P<0.05) and negatively correlated with change in PINP and Sbeta-CTX at 1 and 6 months. In addition, in the alendronate group, the increase in LS BMD was negatively correlated with change in Sbeta-CTX at 1 month (P<0.05). Increases in BMD at the spine and hip were independent of baseline bone turnover in the teriparatide group, while increases in hip BMD were dependent on baseline bone turnover in the alendronate group. With both therapies, early changes in some bone turnover markers were correlated with 18-month gains in BMD in patients with GIO.

Lack of Bone Neoplasms and Persistence of Bone Efficacy in Cynomolgus Macaques After Long‐Term Treatment With Teriparatide [rhPTH(1‐34)]

In rats, teriparatide [rhPTH(1‐34)] causes marked increases in bone mass and osteosarcoma. In primates, teriparatide causes lesser increases in bone mass, and osteosarcomas have not been reported. Previous studies in primates were not designed to detect bone tumors and did not include a prolonged post‐treatment observation period to determine whether tumors would arise after cessation of treatment. Ovariectomized (OVX), skeletally mature, cynomolgus monkeys (n = 30 per group) were given teriparatide for 18 mo at either 0 or 5 μg/kg/d subcutaneously. After 18 mo of treatment, subgroups of six monkeys from both groups were killed and evaluated, whereas all remaining monkeys entered a 3‐yr observation period in which they did not receive teriparatide. Surveillance for bone tumors was accomplished with plain film radiographs, visual examination of the skeleton at necropsy, and histologic evaluation of multiple skeletal sites. Quantitative assessments of bone mass, architecture, and strength were also performed. After the 18‐mo treatment period, vertebral BMD, BMC, and strength (ultimate load) were increased by 29%, 36%, and 52%, respectively, compared with OVX controls. Proximal femur BMD, BMC, and strength were also increased by 15%, 28% and 33%, respectively. After 3 yr without treatment, no differences in bone mass or strength at the vertebra were observed relative to OVX controls; however, the femoral neck showed significant persistence in stiffness (20%), BMC (14%), and trabecular BV/TV (53%), indicating a retention of teriparatide efficacy at the hip. Radiographs and histology did not identify any bone proliferative lesions or microscopic lesions of osteosarcoma at the end of the treatment or observation period. These data indicate that teriparatide did not induce bone proliferative lesions over a 4.5‐yr interval of observation, including 18 mo of treatment and 3 yr of follow‐up observation. Bone analyses confirmed that teriparatide caused increases in bone mass and strength, consistent with previous studies. During the withdrawal phase, beneficial effects of teriparatide treatment on the vertebra were lost; however, some of the beneficial effects on the proximal femur persisted for 3 yr after cessation of treatment. Although the lack of bone tumors in this study provides some additional reassurance regarding the safety of teriparatide for the primate skeleton, the small group size and other limitations of this, or any other animal study, limit the ability to draw definitive conclusions regarding the risk of bone tumor developments in patients.

Bone formation markers in patients with glucocorticoid-induced osteoporosis treated with teriparatide or alendronate☆

Reduced osteoblast function is a primary defect in glucocorticoid-induced osteoporosis (GIO), and is reflected by decreased biochemical markers of bone formation, such as serum osteocalcin (OC) and procollagen type I N-terminal propeptide (PINP). This analysis compared the effects of teriparatide and alendronate on OC and PINP in patients with GIO. In a double-blind study, women (N=159) and men (N=38) with GIO were randomized to either teriparatide 20 mug/day by subcutaneous injection or to alendronate 10 mg/day orally. OC and PINP were measured in fasting-state serum samples obtained at baseline and at 1, 6, 18, and 36 months. Baseline bone formation markers were below the reference interval (low) in 33% of patients for OC and in 4% of patients for PINP. On teriparatide therapy, the median OC and PINP levels increased by 92% and 108%, respectively, and this resulted in only 12% and 1% of patients being low at 6 months. On alendronate therapy, the median OC and PINP levels decreased by 40% and 53%, respectively, and this resulted in 68% and 34% of patients being low at 6 months. We conclude that bone formation as determined by surrogate markers was increased in teriparatide-treated patients with GIO and decreased in alendronate-treated patients with GIO.

Assessment of regional changes in skeletal metabolism following 3 and 18 months of teriparatide treatment

Teriparatide (TPTD) increases skeletal mass, bone turnover markers, and bone strength, but in vivo effects at individual skeletal sites have not been characterized. Quantitative radionuclide imaging studies reflect bone blood flow and osteoblast activity to assess regional changes in bone metabolism. Changes in bone plasma clearance using technetium‐99m methylene diphosphonate (99mTc‐MDP) were quantified and correlated with changes in bone turnover markers in 10 postmenopausal women with osteoporosis. Subjects underwent bone scintigraphy at baseline and 3 and 18 months after initiating TPTD 20 µg/day subcutaneously. Subjects were injected with 600 MBq 99mTc‐MDP, and whole‐body bone scan images were acquired at 10 minutes and 1, 2, 3, and 4 hours. Multiple blood samples were taken between 5 minutes and 4 hours after treatment, and free 99mTc‐MDP was measured using ultrafiltration. The Patlak plot method was used to evaluate whole‐skeleton 99mTc‐MDP plasma clearance (Kbone) and derive regional bone clearance for the calvarium, mandible, spine, pelvis, and upper and lower extremities using gamma camera counts. Bone turnover markers were measured at baseline and 3, 12, and 18 months. Median increases from baseline in whole‐skeleton Kbone were 22.3% (p = .004) and 33.7% (p = .002) at 3 and 18 months, respectively. Regional Kbone values were increased significantly in all six subregions at 3 months and in all subregions except the pelvis at 18 months. Bone markers were increased significantly from baseline at 3 and 18 months and correlated significantly with whole‐skeleton Kbone. This is the first study showing a direct metabolic effect of TPTD at different skeletal sites in vivo, as measured by tracer kinetics.