Dataset Information

Effect of Teriparatide on Bone Formation in the Human Femoral Neck.

ABSTRACT: Teriparatide (TPTD) improves bone mass and microstructure resulting in reduced risk of vertebral and nonvertebral fractures. However, hip bone mineral density improvements are modest and there are no data confirming that TPTD reduces hip fracture risk. To study the effects of TPTD on the proximal femur, we performed a double-blind trial of TPTD vs placebo (PBO) in patients with osteoarthritis from whom femoral neck (FN) samples were obtained at total hip replacement (THR) surgery.Participants were randomly assigned to receive TPTD or PBO for an average of 40 days before THR. Double tetracycline labeling was initiated 21 days prior to THR to allow histomorphometric assessment of bone formation. During the THR, an intact sample of the FN was procured, fixed, and sectioned transversely. Serum levels of bone turnover markers were measured at baseline and during the THR. Standard histomorphometric parameters were measured and calculated on four bone envelopes (cancellous, endocortical, intracortical, and periosteal). The primary outcome measure was bone formation rate/bone surface (BFR/BS).Forty individuals were enrolled (25 women, mean age, 71.5 ± 8.0 y and 15 men, mean age, 68.9 ± 7.7 y). In cancellous and endocortical envelopes, BFR/BS was 100% higher in the TPTD vs PBO group (P < .05). Bone turnover markers measured at the time of THR correlated with BFR/BS.TPTD stimulates bone formation rapidly in cancellous and endocortical envelopes of the FN. Our findings provide a mechanistic basis for TPTD-mediated improvement in FN bone mass and ultimately hip strength. This study is the first demonstration of the effect of any osteoporosis medication on osteoblast activity in the human proximal femur.

SUBMITTER: Cosman F

PROVIDER: S-EPMC4880158 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Effect of Teriparatide on Bone Formation in the Human Femoral Neck.

Cosman Felicia F Dempster David W DW Nieves Jeri W JW Zhou Hua H Zion Marsha M Roimisher Catherine C Houle Yvonne Y Lindsay Robert R Bostrom Mathias M

The Journal of clinical endocrinology and metabolism 20160222 4

<h4>Purpose</h4>Teriparatide (TPTD) improves bone mass and microstructure resulting in reduced risk of vertebral and nonvertebral fractures. However, hip bone mineral density improvements are modest and there are no data confirming that TPTD reduces hip fracture risk. To study the effects of TPTD on the proximal femur, we performed a double-blind trial of TPTD vs placebo (PBO) in patients with osteoarthritis from whom femoral neck (FN) samples were obtained at total hip replacement (THR) surgery ...[more]

PMID: 26900640

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Project description:Teriparatide (TPTD) reduces risk of both vertebral and nonvertebral fracture, but increases bone mineral density (BMD) much more at the spine than the hip. TPTD and mechanical loading may have a synergistic anabolic effect on BMD, which may help explain these site-specific differences. Under normal daily activity, the femoral neck (FN) is under bending, placing one side under tension and the other under compression. We sought to further understand the relationship between mechanical loading and TPTD at the hip by investigating the effect of tensile versus compressive loading on TPTD stimulated bone formation indices in the human FN. Thirty-eight patients receiving total hip replacements for osteoarthritis were randomized to receive placebo (PBO) or TPTD for a mean treatment duration of 6 weeks prior to surgery, and double tetracycline labeling was administered to allow assessment of bone formation. The FN was harvested during surgery and analyzed for dynamic bone formation indices in the compressive and tensile regions of the endocortical and periosteal envelopes. Regression models relating outcome measures to patient characteristics including sex, age, body weight, and FN geometry were also analyzed. Overall, bone formation was higher with TPTD versus placebo on the endocortical surface, but not the periosteal surface. The level of bone formation in both TPTD and placebo groups was greater on the tensile endocortical surface and the compressive periosteal surface. There was a trend toward decreased endocortical eroded surface with TPTD in the compressive but not the tensile region. Patient age and sex explained the greatest variability in endocortical bone formation, and patient body mass and sex explained the greatest variability in periosteal bone formation. Our data represent the first dynamic comparison of teriparatide treatment under two loading modalities in human FN samples. Future work could determine whether specific hip loading intervention could amplify the benefits of teriparatide on the hip in clinical settings.

Project description:Intermittent administration of PTH type 1 receptor (PTH1R) agonists increases bone remodeling, with greater stimulation of bone formation relative to bone resorption causing net gains in bone mass. This pharmacodynamic feature underlies the bone-building effects of teriparatide and abaloparatide, the only PTH1R agonists approved to reduce osteoporotic fracture risk in postmenopausal women. This study in 8-week-old female mice compared bone resorption and formation responses to these agents delivered at the same 10 μg/kg dose, and a 40 μg/kg abaloparatide dose was also included to reflect its 4-fold higher approved clinical dose. Peptides or vehicle were administered by daily supra-calvarial subcutaneous injection for 12 days, and local (calvarial) and systemic (L5 vertebral and tibial) responses were evaluated by histomorphometry. Terminal bone histomorphometry data indicated that calvarial resorption cavities were similar in both abaloparatide groups versus vehicle controls, whereas the teriparatide group had more calvarial resorption cavities compared with the vehicle or abaloparatide 40 μg/kg groups. The bone resorption marker serum CTX was significantly lower in the abaloparatide 40 μg/kg group and similar in the other two active treatment groups compared with vehicle controls. Both peptides increased trabecular bone formation rate (BFR) in L5 and proximal tibia versus vehicle, and L5 BFR was higher with abaloparatide 40 μg/kg versus teriparatide. At the tibial diaphysis, periosteal BFR was higher with abaloparatide 40 μg/kg versus vehicle or teriparatide, and endocortical BFR was higher with teriparatide but not with abaloparatide 10 or 40 μg/kg versus vehicle. Few differences in structural or microarchitectural bone parameters were observed with this brief duration of treatment. In summary, calvarial bone resorption cavity counts were higher in the teriparatide group versus the vehicle and abaloparatide 40 μg/kg groups, and the abaloparatide 40 μg/kg group had lower serum CTX versus vehicle. L5 and tibial trabecular bone formation indices were higher in all three active treatment groups versus vehicle. The abaloparatide 40 μg/kg group had higher L5 trabecular BFR and tibial periosteal BFR versus teriparatide, whereas tibial endocortical BFR was higher with teriparatide but not abaloparatide. Together, these findings in female mice indicate that an improved balance of bone formation versus bone resorption is established shortly after initiating treatment with abaloparatide.

Project description:BackgroundGenome-wide association studies (GWASs) routinely identify loci associated with risk factors for osteoporosis. However, GWASs with relatively small sample sizes still lack sufficient power to ascertain the majority of genetic variants with small to modest effect size, which may together truly influence the phenotype. The loci identified only account for a small percentage of the heritability of osteoporosis. This study aims to identify novel genetic loci associated with DXA-derived femoral neck (FNK) bone mineral density (BMD) and quantitative ultrasound of the heel calcaneus estimated BMD (eBMD), and to detect shared/causal variants for the two traits, to assess whether the SNPs or putative causal SNPs associated with eBMD were also associated with FNK-BMD.MethodsNovel loci associated with eBMD and FNK-BMD were identified by the genetic pleiotropic conditional false discovery rate (cFDR) method. Shared putative causal variants between eBMD and FNK-BMD and putative causal SNPs for each trait were identified by the colocalization method. Mendelian randomization analysis addresses the causal relationship between eBMD/FNK-BMD and fracture.ResultsWe identified 9,500 (cFDR < 9.8E-6), 137 (cFDR < 8.9E-4) and 124 SNPs associated with eBMD, FNK-BMD, and both eBMD and FNK-BMD, respectively, with 37 genomic regions where there was a SNP that influences both eBMD and FNK-BMD. Most genomic regions only contained putative causal SNPs associated with eBMD and 3 regions contained two distinct putative causal SNPs influenced both traits, respectively. We demonstrated a causal effect of FNK-BMD/eBMD on fracture.ConclusionMost of SNPs or putative causal SNPs associated with FNK-BMD were also associated with eBMD. However, most of SNPs or putative causal SNPs associated with eBMD were not associated with FNK-BMD. The novel variants we identified may help to account for the additional proportion of variance of each trait and advance our understanding of the genetic mechanisms underlying osteoporotic fracture.

Dataset Information

Effect of Teriparatide on Bone Formation in the Human Femoral Neck.

Publications

Effect of Teriparatide on Bone Formation in the Human Femoral Neck.

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