Effects of teriparatide on fusion rates in patients undergoing complex foot and ankle arthrodesis

BackgroundHere, we determined whether teriparatide treatment would increase fusion rates after foot and ankle arthrodesis by comparing treatment results between patients with high-risk factors for nonunion who received teriparatide against those who did not.MethodsWe retrospectively reviewed 66 consecutive patients who underwent foot and ankle arthrodesis. The inclusion criterion was the presence of at least one of the following risk factors for nonunion after previous foot and ankle arthrodesis: deformity, bone defects, avascular necrosis, and nonunion. Sixteen patients were finally enrolled and divided into 2 groups: 8 patients received teriparatide treatment after fusion surgery (PTH group), and 8 patients did not (control group).ResultsThe fusion rate was significantly greater in the PTH group than in the control group (100% vs 50%). Four patients in the control group developed nonunion, 3 of whom underwent revision fusion; however, all patients received the teriparatide treatment after revision surgery and subsequently achieved union. No significant differences in demographics, fusion sites, and complication rates were found.ConclusionThough the sample size was small, the current study suggests that teriparatide administration may improve fusion rates in patients with high-risk factors for nonunion after foot and ankle arthrodesis.     

Degradation of teriparatide by gastro-intestinal proteolytic enzymes

Teriparatide, a recombinant parathyroid hormone (1–34) is the first approved agent for the treatment of osteoporosis that stimulates new bone formation. Currently, the drug is administered daily by s.c. injection. Because of the obvious advantages of oral teriparatide administration, the development of such a delivery system would be of great benefit. Besides other barriers, the enzymatic barrier caused by gastro-intestinal (GI) proteolytic enzymes is believed to be responsible for negligible teriparatide oral bioavailability. It was therefore the aim of the study to evaluate the stability of teriparatide towards a variety of GI proteases under physiological conditions. Results indicate that teriparatide is entirely degraded by trypsin, chymotrypsin and pepsin within 5 min. In contrast, even after 3 h of incubation with elastase about 85% of undegraded teriparatide could still be detected. Within an incubation period of 3 h in the presence of rat small intestinal mucosa, approximately half of the teriparatide was degraded. Experiments with isolated aminopeptidase N demonstrated that this membrane bound peptidase is primarily involved in the degradation process. Results gained from and recorded in this study provide a precise characterisation of the enzymatic barrier for oral teriparatide administration and represents a prerequisite for the development of oral teriparatide delivery systems.     

Parathyroid hormone and bone biomechanics

Parathyroid hormone (PTH) treatment, either in the form of teriparatide or recombinant human PTH(1–34), reduces the fracture risk of osteoporotic women by enhancing both structural and material biomechanical properties. Cortical bone thickness and cross-sectional moment of inertia increase because of new bone formation on periosteal and endocortical surfaces. Intracortical porosity is increased yet preferential localization near the endocortical surface limits any negative biomechanical effects. Greater trabecular bone volume results from a positive basic multicellular unit bone balance and renewed modeling. Initial increases in trabecular thickness are eventually reduced as a result of trabecular tunneling, increasing trabecular number, and connectivity. These geometrical and architectural alterations are the predominant mechanism by which PTH increases structural strength, stiffness, and energy absorption. PTH also positively alters material-level strength, modulus, and toughness. These changes are counterintuitive based on known effects of decreasing average tissue mineralization and increasing tissue heterogeneity. This combination of enhanced structural and material biomechanical properties makes PTH an effective treatment for reducing fracture risk despite smaller gains in bone mineral density compared to other osteoporosis agents.     

The Effect of Prior Bisphosphonate Exposure on the Treatment Response to Teriparatide in Clinical Practice

Our objective was to determine the effect of prior bisphosphonate exposure on the treatment response to teriparatide. All patients started on teriparatide in our hospital are entered into a database. All patients who had at least 12 months’ treatment were identified. Patients were divided into two groups depending on whether or not they had prior bisphosphonate exposure, and the response to teriparatide was compared using procollagen of type 1 N-terminal propeptide (P1NP) and bone mineral density (BMD). Fifty-two patients had been treated for at least 12 months, 38 with prior bisphosphonate exposure and 14 without. The mean duration of bisphosphonate treatment was 67 months, discontinued a mean of 1 month previously. P1NP increased significantly at 3 and 6 months in both groups. However, those without previous bisphosphonate treatment had a higher baseline P1NP (49 vs. 30 μg/L, P < 0.01), and this remained higher at 3 months (109 vs. 71 μg/L, P = 0.10) and 6 months (183 vs. 126 μg/L, P = 0.06), although the difference was not significant. In the prior bisphosphonate and bisphosphonate naive groups, respectively, the change in spinal BMD was 9.0% and 7.8% (P = 0.54) at 12 months and 9.8% and 6.1% (P = 0.30) at 18 months. The respective change in hip BMD was 1.0% and −0.3% (P = 0.36) at 12 months and 2.8% and 1.3% (P = 0.44) at 18 months. There was a trend toward a smaller but still significant increase in P1NP in response to teriparatide in bisphosphonate-treated patients. Although this suggests a blunting of the anabolic effects, in our clinic population this did not result in a reduction in BMD gain.     

Relationship between duration of teriparatide therapy and clinical outcomes in postmenopausal women with osteoporosis

Summary  The extent to which fracture protection and safety varies with increasing time on teriparatide [rhPTH(1-34)] therapy is a clinically relevant unanswered question. In postmenopausal women with osteoporosis, increased duration of teriparatide versus placebo treatment was associated with a progressive decrease in the rates of nonvertebral fragility fractures and back pain. Introduction  The impact of duration of teriparatide [rhPTH(1-34)] therapy on patient outcomes is a relevant unanswered question. Methods  Postmenopausal women with osteoporosis were randomized to once-daily subcutaneous injection with placebo (N = 544), teriparatide 20 μg (TPTD20; N = 541), or teriparatide 40 μg (TPTD40; N = 552) plus calcium and vitamin D supplementation. The time to first nonvertebral fragility fracture and new or worsening back pain following treatment initiation was analyzed using Cox partial likelihood regression treating time on therapy as a linear, time-dependent covariate. Results  Compared with placebo, the relative hazard for nonvertebral fragility fractures decreased by 7.3% for each additional month of TPTD20 [hazard ratio = 0.927, 95% CI (0.876 to 0.982), p = 0.009] and by 7.6% for each additional month of TPTD40 [hazard ratio = 0.924, 95% CI (0.871 to 0.981), p = 0.009]. Clinical vertebral fractures appeared to increase over time in the placebo group and occurred primarily in the first time interval in the teriparatide treatment groups. Compared with placebo, the relative hazard of back pain was decreased by 8.3% for each additional month of TPTD20 [hazard ratio = 0.920, 95% CI (0.902 to 0.939), p < 0.001] and 8.7% for each additional month of TPTD40 [hazard ratio = 0.917, 95% CI (0.898 to 0.935), p < 0.001]. Conclusions  These findings suggest increased nonvertebral fracture protection, reduced back pain, and reduced occurrence of side effects with longer duration of teriparatide therapy. Some of these findings were presented at the 67th Annual Scientific Meeting of the American College of Rheumatology in Orlando, Florida, October 23–28, 2003 and at the 31st European Symposium on Calcified Tissues in Nice, France, June 5–9, 2004.     

Teriparatide in postmenopausal women with osteoporosis and mild or moderate renal impairment

Introduction The prevalence of both osteoporosis and renal impairment increases with age. Methods Using data from the Fracture Prevention Trial, the safety and efficacy of teriparatide [rhPTH(1–34)] in postmenopausal women with osteoporosis and renal impairment were explored. Patients were required to have serum creatinine concentrations ≤2.0 mg/dl and normal serum parathyroid hormone (PTH) concentrations and were randomized to receive daily subcutaneous injections of placebo or teriparatide 20 or 40 mcg/day. Glomerular filtration rate (GFR) was estimated using the Cockcroft–Gault equation. Patients were defined from baseline assessments to have normal (GFR ≥80 ml/min), mildly impaired (GFR 50–79 ml/min), or moderately impaired (GFR 30–49 ml/min) renal function for bone mineral density (BMD) and amino-terminal extension peptide of procollagen type 1 (PINP) analyses, and normal (GFR ≥80 ml/min) or impaired (GFR <80 ml/min) renal function for fracture analyses. Results and conclusions Compared with patients with normal renal function, patients with renal impairment were older, shorter, weighed less, had been postmenopausal longer, and had lower baseline lumbar spine and femoral neck BMD. Compared with placebo, teriparatide significantly increased PINP and lumbar spine and femoral neck BMD within each renal function subgroup, and there was no evidence that these increases were altered by renal insufficiency (each treatment-by-subgroup interaction p>0.05). Similarly, teriparatide-mediated vertebral and nonvertebral fracture risk reductions were similar and did not differ significantly between patients with normal or impaired renal function (treatment-by-subgroup interactions p>0.05). The incidences of treatment-emergent and renal-related adverse events were consistent across treatment assignment in the normal, mildly impaired, and moderately impaired renal function subgroups. Teriparatide induced changes in mean GFR were unaffected by baseline renal function (treatment-by-renal function interaction p>0.05 for normal, mildly impaired, or moderately impaired subgroups). Patients in all renal function categories treated with teriparatide 20 or 40 mcg had an increased incidence of 4–6-h postdose serum calcium >10.6 mg/dl (the upper limit of normal) versus placebo; however, teriparatide 20 mcg/day was not associated with significantly increased incidence of 4–6-h postdose serum calcium >11 mg/dl in any renal function category. Teriparatide therapy was associated with increased incidence of elevated uric acid, with the incidences being highest in patients with moderately impaired renal function and in those receiving teriparatide 40 mcg/day. Even so, adverse event data did not suggest an increased incidence of gout or arthralgia or of nephrolithiasis events in teriparatide-treated patients with normal, mild, or moderate renal impairment. This study was supported by Eli Lilly and Company.     

Bone and glucocorticoids

Corticosteroid-induced osteoporosis is the most common form of secondary osteoporosis and the most frequent cause of osteoporosis in young people. Bone loss and fracture risk increase rapidly after the initiation of corticosteroid therapy and are proportional to dose and treatment duration. The increase in fracture risk is not fully assessed by bone mineral density measurement, as it is also related to impaired bone quality and increased risk of falls. Prevention should be considered in all patients beginning corticosteroid therapy, especially as the underlying inflammation in itself impairs bone quality. Bisphosphonates and teriparatide have shown efficacy in the treatment of corticosteroid-induced osteoporosis. Several national and international guidelines are available to improve management of corticosteroid-induced osteoporosis, which remains inadequate. Duration of anti-osteoporotic treatment should be discussed at the individual level, depending on the subject's characteristics and on the progression of the underlying inflammation.     

Effect of teriparatide use on bone mineral density and spinal fusion: a narrative review of animal models

Purpose of the study: Teriparatide (Human recombinant Parathyroid Hormone 1-34) is an anabolic agent that is frequently used in patients with osteoporosis and has been extensively investigated with animal model and clinical studies in current literature. The purpose of the study was to evaluate the impact of teriparatide on bone mineral density and fusion.

Materials and methods: The findings from preclinical studies that have investigated the role of teriparatide in animal models are summarized in presented review.

Results: Overall, the studies show an improvement in bone mineral density and increased fusion rates for osteoporotic animals undergoing spine fusion with teriparatide use.

Conclusion: Further studies should be conducted for unanswered questions, such as teriparatide use before surgery, the effect on cervical fusion and surgery related complications.