Emmett V. Glass

Effects of teriparatide and alendronate on vertebral strength as assessed by finite element modeling of QCT scans in women with osteoporosis.

FE modeling was used to estimate the biomechanical effects of teriparatide and alendronate on lumbar vertebrae. Both treatments enhanced predicted vertebral strength by increasing average density. This effect was more pronounced for teriparatide, which further increased predicted vertebral strength by altering the distribution of density within the vertebra, preferentially increasing the strength of the trabecular compartment.

Combination Teriparatide and Raloxifene Therapy for Postmenopausal Osteoporosis: Results From a 6-Month Double-Blind Placebo-Controlled Trial†‡

We compared combination treatment with teriparatide plus raloxifene with teriparatide alone in women with postmenopausal osteoporosis in a 6‐month double‐blind, placebo‐controlled trial that measured biochemical markers of bone turnover and BMD. Markers of bone formation and spine BMD increased similarly with teriparatide alone and combination therapy. However, combination therapy induced a significantly smaller increase in bone resorption versus teriparatide alone and significantly increased total hip BMD versus baseline.

Teriparatide (PTH(1-34)) Strengthens the Proximal Femur of Ovariectomized Nonhuman Primates Despite Increasing Porosity

OVX monkeys treated for 18 months with 1 or 5 μg/kg/d teriparatide [PTH (1–34)] had significantly stronger proximal femora relative to ovariectomized controls. Teriparatide enhancement of cortical area, cortical width, and trabecular bone volume seemed to more than compensate for the dose‐dependent increase in cortical porosity. Beneficial effects of teriparatide treatment on the proximal femur persisted beyond the treatment period and may extend to the marrow.

Effects of Teriparatide in Postmenopausal Women with Osteoporosis on Prior Alendronate or Raloxifene: Differences between Stopping and Continuing the Antiresorptive Agent

OBJECTIVE The aim of the study was to assess adding vs. switching to teriparatide 20 microg/d in patients on alendronate or raloxifene. DESIGN We conducted a randomized, open-label trial. PATIENTS AND INTERVENTIONS Postmenopausal women with osteoporosis on alendronate or raloxifene for at least 18 months added teriparatide (Add groups) or switched to teriparatide (Switch groups) for 18 months. MAIN OUTCOME MEASURES We measured bone turnover markers (BTM) and bone mineral density (BMD). RESULTS In the alendronate stratum, increases in BTM were smaller in the Add vs. Switch group [6-month PINP (64 vs. 401%); bone ALP (15 vs. 71%); betaCTX (27 vs. 250%); all P < 0.001]. However, at 6 months, total hip BMD increased more in the Add vs. Switch group (1.4 vs. -0.8%; P = 0.002). In the Add vs. Switch group, 18-month BMD increments were higher in lumbar spine (8.4 vs. 4.8%; P = 0.003) and total hip (3.2 vs. 0.9%; P = 0.02), but not in femoral neck (2.7 vs. 2.3%; P = 0.75). In the raloxifene stratum, increases in BTM were also smaller in the Add vs. Switch group [6-month PINP (131 vs. 259%; P < 0.001), bone ALP (31 vs. 44%; P = 0.035), and betaCTX (67 vs. 144%; P = 0.001)]. At 6 months, total hip BMD increase was greater in the Add vs. Switch group (1.8 vs. 0.5%; P = 0.028). At 18 months, increases in lumbar spine (9.2 vs. 8.1%), total hip (2.8 vs. 1.8%), and femoral neck (3.8 vs. 2.2%) were not significantly different between groups. CONCLUSIONS In women with osteoporosis treated with antiresorptives, greater bone turnover increases were achieved by switching to teriparatide, whereas greater BMD increases were achieved by adding teriparatide.

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.

The effects of teriparatide on the incidence of back pain in postmenopausal women with osteoporosis.

ABSTRACT Objectives: Back pain is a major cause of suffering, disability, and cost. The risk of developing back pain was assessed following treatment with teriparatide [rh(PTH 1–34)] in postmenopausal women with osteoporosis. Research design and methods: A secondary analysis of back pain findings from the global, multi-site Fracture Prevention Trial was conducted where postmenopausal women with prevalent vertebral fractures were administered teriparatide 20 µg ( n = 541) or placebo ( n = 544) for a median of 19 months. Treatment-emergent back pain data were collected during adverse event monitoring, and spine radiographs were obtained at baseline and study endpoint. Main outcome measures: The risk of back pain stratified by severity of new or worsening back pain and the risk of back pain associated with both number and severity of new vertebral fractures. Results: Women randomized to teriparatide 20 µg had a 31% reduced relative risk of moderate or severe back pain (16.5% vs. 11.5%, P = 0.016) and a 57% reduced risk of severe back pain (5.2% vs. 2.2%, P = 0.011). Compared with placebo, teriparatide-treated patients experienced reduced relative risk of developing back pain associated with findings of: one or more new vertebral fractures by 83% (6.5% vs. 1.1%, P < 0.001), two or more new vertebral fractures by 91% (2.5% vs. 0.20%, P = 0.004), and one or more new moderate or severe vertebral fractures by 100% (5.1% vs. 0.0%, P < 0.001). Conclusions: Teriparatide-treated women had reduced risk for moderate or severe back pain, severe back pain, and back pain associated with vertebral fractures. The mechanism of the back pain reduction likely includes the reduction both in severity and number of new vertebral fractures.

Teriparatide and raloxifene reduce the risk of new adjacent vertebral fractures in postmenopausal women with osteoporosis. Results from two randomized controlled trials.

BACKGROUND Vertebral fractures increase the risk of new vertebral fractures; however, we are not aware of any study addressing the risk of new vertebral fractures adjacent to existing vertebral fractures. Therefore, we sought to determine the influence of the number and severity of prevalent (preexisting) vertebral fractures on the risk of new adjacent vertebral fractures and to determine whether teriparatide (rhPTH [recombinant human parathyroid hormone] [1-34]) or raloxifene treatment reduces the incidence of adjacent vertebral fractures in postmenopausal women with osteoporosis. METHODS Data from the Fracture Prevention Trial and the Multiple Outcomes of Raloxifene Evaluation trial were analyzed to determine the incidences of new adjacent and new nonadjacent vertebral fractures in the placebo groups and the effect of treatment with raloxifene and teriparatide on the incidence of new adjacent vertebral fractures as compared with that of new nonadjacent vertebral fractures. RESULTS Of 1226 untreated postmenopausal women with one or more prevalent vertebral fractures at baseline, 196 (16.0%) had a total of 292 new vertebral fractures during the two-year follow-up period, with 108 (8.8%) of the 1226 women having at least one new fracture adjacent to a prevalent fracture. Of the 292 new vertebral fractures, 136 (47%) were adjacent to a previously existing vertebral fracture. The risk of a new adjacent vertebral fracture was 2.5-fold higher than the risk of a new nonadjacent vertebral fracture (4.03% compared with 1.59%). The incidence of new adjacent vertebral fractures increased with both the number and the severity of prevalent vertebral fractures. Teriparatide reduced the risk of any new, new adjacent, and new nonadjacent vertebral fractures by 72%, 75%, and 70%, respectively, compared with the rates in the placebo group. Similarly, compared with the placebo, raloxifene treatment reduced the risk of any new vertebral fracture, new adjacent vertebral fracture, and new nonadjacent vertebral fracture by 54%, 54%, and 53%, respectively. CONCLUSIONS In untreated postmenopausal women with osteoporosis, nearly half of the incident vertebral fractures occur adjacent to an existing vertebral fracture. Both teriparatide and raloxifene can significantly reduce the occurrence of new adjacent and nonadjacent vertebral fractures.

Effects of Teriparatide in Postmenopausal Women With Osteoporosis on Prior Alendronate or Raloxifene: Differences Between Stopping and Continuing the Antiresorptive Agent

A number of studies have investigated combined use of anabolic therapy with teriparatide (recombinant human parathyroid hormone [PTH]) and antiresorptive therapy (alendronate or raloxifene) in postmenopausal women at high-risk of fracture, but the benefits are unclear due to conflicting results. This randomized, open-label trial investigated the effects of switching to teriparatide (Switch group) or adding this anabolic (Add group) on bone turnover markers (BTMs) and bone mineral density (BMD) in 198 postmenopausal women with osteoporosis who had been on alendronate or raloxifene for 18 months. Increases in BTMs were less in the alendronate Add group compared to the Switch group at 6 months: median increases in BTMs from baseline in the Add versus Switch group were 64% versus 401% for PINP; 15 versus 71% in bone ALP; and 27% versus 250% in ss-CTX (all P < 0.001). Total hip BMD increased more at 6 months with alendronate, however, in the Add versus Switch group (1.4% vs.-0.8%; P < 0.01). At 18 months, increases in BMD with alendronate were higher in the Add versus Switch group in the lumbar spine (8.4% vs. 4.8%; P < 0.003) and total hip (3.2% vs. 0.9%; P < 0.02). With respect to the raloxifene stratum, BTM data at 6 months were similar to those of the alendronate stratum in 2 respects. First, increases in the BTMs of the raloxifene stratum were also smaller in the Add than in the Switch group (131% vs. 259% in the PINP, P < 0.001; 31% vs. 44% in bone ALP, P < 0.035; and 67% vs. 144% in the ss-CTX, P < 0.001). Second, the total hip BMD increase was greater in the Add group (1.8% vs. 0.5%; P = 0.028). In contrast to alendronate, no significant differences between the groups were found at 18 months in lumbar spine (9.2% vs. 8.1%) or total hip BMD (2.8% vs. 1.8%). The between-group differences in femoral neck BMD were not significant in either stratum at 6 or 18 months. Adverse reactions and overall safety were similar in both groups. These findings show that in women with osteoporosis, switching to teriparatide produces greater increases in BTMs than adding this anabolic agent to an antiresorptive, whereas adding confers greater increases in BMD.

Measuring serum calcium before and after teriparatide treatment: authors’ response

Dear Editor, We appreciate the interest of Dr. Minisola et al. in our paper. First, they question whether there may have been a technical problem with the serum calcium assay. We took considerable efforts to avoid such technical problems. Specifically, the protocol specified that patients were not to fast and that they were to drink 6–8 oz of water in the morning prior to their visits. During blood sample collection, sites were to limit tourniquet time and the first tube collected was used for serum calcium assessment. The serum calcium assays were performed by Mayo Clinic Laboratories. The second discussion point is related to the inclusion of some patients with serum calcium concentrations above the normal range at randomization. As noted, eight patients had a serum calcium level in excess of the normal range at visit 1 (2.52 mmol/L or 10.1 mg/dL based on the Mayo Clinic reference range); seven of these patients had a retest value which was within the reference range before continuing. The eighth patient was allowed to continue with baseline serum calcium concentration 0.05 mmol/L above the reference range. The third question related to a possible relationship between serum calcium and urinary calcium excretion. There were no statistically significant correlations between baseline serum calcium and urinary calcium excretion at baseline or after 1, 3, or 6 months of teriparatide treatment. However, there were weak but statistically significant correlations between serum calcium and urinary calcium excretion after 1, 3, and 6 months of teriparatide treatment. Osteoporos Int (2008) 19:1809 DOI 10.1007/s00198-008-0733-9