Kelly Krohn

Teriparatide for acceleration of fracture repair in humans: A prospective, randomized, double‐blind study of 102 postmenopausal women with distal radial fractures

Animal experiments show a dramatic improvement in skeletal repair by teriparatide. We tested the hypothesis that recombinant teriparatide, at the 20 µg dose normally used for osteoporosis treatment or higher, would accelerate fracture repair in humans. Postmenopausal women (45 to 85 years of age) who had sustained a dorsally angulated distal radial fracture in need of closed reduction but no surgery were randomly assigned to 8 weeks of once‐daily injections of placebo (n = 34) or teriparatide 20 µg (n = 34) or teriparatide 40 µg (n = 34) within 10 days of fracture. Hypotheses were tested sequentially, beginning with the teriparatide 40 µg versus placebo comparison, using a gatekeeping strategy. The estimated median time from fracture to first radiographic evidence of complete cortical bridging in three of four cortices was 9.1, 7.4, and 8.8 weeks for placebo and teriparatide 20 µg and 40 µg, respectively (overall p = .015). There was no significant difference between the teriparatide 40 µg versus placebo groups (p = .523). In post hoc analyses, there was no significant difference between teriparatide 40 µg versus 20 µg (p = .053); however, the time to healing was shorter in teriparatide 20 µg than placebo (p = .006). The primary hypothesis that teriparatide 40 µg would shorten the time to cortical bridging was not supported. The shortened time to healing for teriparatide 20 µg compared with placebo still may suggest that fracture repair can be accelerated by teriparatide, but this result should be interpreted with caution and warrants further study.

Effects of Teriparatide Versus Alendronate for Treating Glucocorticoid-Induced Osteoporosis Thirty-Six-Month Results of a Randomized, Double-Blind, Controlled Trial

OBJECTIVE To compare the bone anabolic drug teriparatide (20 microg/day) with the antiresorptive drug alendronate (10 mg/day) for treating glucocorticoid-induced osteoporosis (OP). METHODS This was a 36-month, randomized, double-blind, controlled trial in 428 subjects with OP (ages 22-89 years) who had received > or =5 mg/day of prednisone equivalent for > or =3 months preceding screening. Measures included changes in lumbar spine and hip bone mineral density (BMD), changes in bone biomarkers, fracture incidence, and safety. RESULTS Increases in BMD from baseline were significantly greater in the teriparatide group than in the alendronate group, and at 36 months were 11.0% versus 5.3% for lumbar spine, 5.2% versus 2.7% for total hip, and 6.3% versus 3.4% for femoral neck (P < 0.001 for all). In the teriparatide group, median percent increases from baseline in N-terminal type I procollagen propeptide (PINP) and osteocalcin (OC) levels were significant from 1 to 36 months (P < 0.01), and increases in levels of C-terminal telopeptide of type I collagen (CTX) were significant from 1 to 6 months (P < 0.01). In the alendronate group, median percent decreases in PINP, OC, and CTX were significant by 6 months and remained below baseline through 36 months (P < 0.001). Fewer subjects had vertebral fractures in the teriparatide group than in the alendronate group (3 [1.7%] of 173 versus 13 [7.7%] of 169; P = 0.007), with most occurring during the first 18 months. There was no significant difference between groups in the incidence of nonvertebral fractures (16 [7.5%] of 214 subjects taking teriparatide versus 15 [7.0%] of 214 subjects taking alendronate; P = 0.843). More subjects in the teriparatide group (21%) versus the alendronate group (7%) had elevated predose serum calcium concentrations (P < 0.001). CONCLUSION Our findings indicate that subjects with glucocorticoid-induced OP treated with teriparatide for 36 months had greater increases in BMD and fewer new vertebral fractures than subjects treated with alendronate.

Osteoporosis Medication Use After Hip Fracture in U.S. Patients Between 2002 and 2011

Hip fractures are common, morbid, costly, and associated with subsequent fractures. Historically, postfracture osteoporosis medication use rates have been poor, but have not been recently examined in a large‐scale study. We conducted a retrospective, observational cohort study based on U.S. administrative insurance claims data for beneficiaries with commercial or Medicare supplemental health insurance. Eligible participants were hospitalized for hip fracture between January 1, 2002, and December 31, 2011, and aged 50 years or older at admission. The outcome of interest was osteoporosis medication use within 12 months after discharge. Patients were censored after 12 months, loss to follow‐up, or a medical claim for cancer or Pagets disease, whichever event occurred first. During the study period, 96,887 beneficiaries met the inclusion criteria; they had a mean age of 80 years and 70% were female. A total of 34,389 (35.5%) patients were censored before reaching 12 months of follow‐up. The Kaplan‐Meier estimated probability of osteoporosis medication use within 12 months after discharge was 28.5%. The rates declined significantly from 40.2% in 2002, to 20.5% in 2011 (p for trend <0.001). In multivariable Cox proportional hazards models, a number of patient characteristics were associated with reduced likelihood of osteoporosis medication use, including older age and male gender. However, the predictor most strongly and most positively associated with osteoporosis medication use after fracture was osteoporosis medication use before the fracture (hazard ratio = 7.45; 95% confidence interval [CI], 7.23–7.69). Most patients suffering a hip fracture do not use osteoporosis medication in the subsequent year and treatment rates have worsened.

Femoral strength in osteoporotic women treated with teriparatide or alendronate.

To gain insight into the clinical effect of teriparatide and alendronate on the hip, we performed non-linear finite element analysis of quantitative computed tomography (QCT) scans from 48 women who had participated in a randomized, double-blind clinical trial comparing the effects of 18-month treatment of teriparatide 20 μg/d or alendronate 10mg/d. The QCT scans, obtained at baseline, 6, and 18 months, were analyzed for volumetric bone mineral density (BMD) of trabecular bone, the peripheral bone (defined as all the cortical bone plus any endosteal trabecular bone within 3 mm of the periosteal surface), and the integral bone (both trabecular and peripheral), and for overall femoral strength in response to a simulated sideways fall. At 18 months, we found in the women treated with teriparatide that trabecular volumetric BMD increased versus baseline (+4.6%, p<0.001), peripheral volumetric BMD decreased (-1.1%, p<0.05), integral volumetric BMD (+1.0%, p=0.38) and femoral strength (+5.4%, p=0.06) did not change significantly, but the ratio of strength to integral volumetric BMD ratio increased (+4.0%, p=0.04). An increase in the ratio of strength to integral volumetric BMD indicates that overall femoral strength, compared to baseline, increased more than did integral density. For the women treated with alendronate, there were small (<1.0%) but non-significant changes compared to baseline in all these parameters. The only significant between-treatment difference was in the change in trabecular volumetric BMD (p<0.005); related, we also found that, for a given change in peripheral volumetric BMD, femoral strength increased more for teriparatide than for alendronate (p=0.02). We conclude that, despite different compartmental volumetric BMD responses for these two treatments, we could not detect any overall difference in change in femoral strength between the two treatments, although femoral strength increased more than integral volumetric BMD after treatment with teriparatide.

Hip and spine strength effects of adding versus switching to teriparatide in postmenopausal women with osteoporosis treated with prior alendronate or raloxifene

Many postmenopausal women treated with teriparatide for osteoporosis have previously received antiresorptive therapy. In women treated with alendronate (ALN) or raloxifene (RLX), adding versus switching to teriparatide produced different responses in areal bone mineral density (aBMD) and biochemistry; the effects of these approaches on volumetric BMD (vBMD) and bone strength are unknown. In this study, postmenopausal women with osteoporosis receiving ALN 70 mg/week (n = 91) or RLX 60 mg/day (n = 77) for ≥18 months were randomly assigned to add or switch to teriparatide 20 µg/day. Quantitative computed tomography scans were performed at baseline, 6 months, and 18 months to assess changes in vBMD; strength was estimated by nonlinear finite element analysis. A statistical plan specifying analyses was approved before assessments were completed. At the spine, median vBMD and strength increased from baseline in all groups (13.2% to 17.5%, p < 0.01); there were no significant differences between the Add and Switch groups. In the RLX stratum, hip vBMD and strength increased at 6 and 18 months in the Add group but only at 18 months in the Switch group (Strength, Month 18: 2.7% Add group, p < 0.01 and 3.4% Switch group, p < 0.05). In the ALN stratum, hip vBMD increased in the Add but not in the Switch group (0.9% versus –0.5% at 6 months and 2.2% versus 0.0% at 18 months, both p ≤ 0.004 group difference). At 18 months, hip strength increased in the Add group (2.7%, p < 0.01) but not in the Switch group (0%); however, the difference between groups was not significant (p = 0.076). Adding or switching to teriparatide conferred similar benefits on spine strength in postmenopausal women with osteoporosis pretreated with ALN or RLX. Increases in hip strength were more variable. In RLX‐treated women, strength increased more quickly in the Add group; in ALN‐treated women, a significant increase in strength compared with baseline was seen only in the Add group.

Baseline Glucocorticoid Dose and Bone Mineral Density Response with Teriparatide or Alendronate Therapy in Patients with Glucocorticoid-induced Osteoporosis

Objective. This post-hoc analysis studied the effect of baseline glucocorticoid dose on the 18-month bone mineral density (BMD) response to teriparatide 20 μg/day or alendronate 10 mg/day in 387 patients with glucocorticoid-induced osteoporosis (GIO) from a randomized, double-blind trial. Methods. Lumbar spine (LS), femoral neck (FN), and total hip (TH) BMD were measured at baseline and 18 months. Mean baseline glucocorticoid dose was categorized as low (≤ 5 mg/day), medium (> 5 and < 15 mg/day), or high (≥ 15 mg/day). Results. Baseline LS, FN, and TH BMD were similar between groups, and between glucocorticoid dose categories within each group. LS BMD increases at the low, medium, and high glucocorticoid doses were 8.1%, 6.6%, and 4.6%, respectively, with teriparatide, and 3.6%, 2.8%, and 2.3% with alendronate. Analyzed as a continuous variable, higher glucocorticoid doses had a negative, but non-significant, effect on the percentage increase in LS BMD in both groups. Glucocorticoid dose did not significantly affect FN or TH BMD increases in either group. Across the 3 glucocorticoid dose categories, the overall LS BMD increases were different for both treatments combined (p = 0.033), but the relative differences between the treatment groups were not different (interaction, p = 0.52). Conclusion. Teriparatide and alendronate increased LS and hip BMD across a range of baseline glucocorticoid doses. LS BMD increases with teriparatide were greater in the low-dose category than in the high-dose category. Overall LS BMD increases were significantly greater with teriparatide compared with alendronate, which may reflect the respective anabolic and antiresorptive mechanisms of action. Clinical Trial Registry Number: NCT00051558.

Vertebral fracture risk is reduced in women who lose femoral neck BMD with teriparatide treatment.

Response to osteoporosis therapy is often assessed by serial BMD testing. Patients who lose BMD without secondary causes of bone loss may be considered to be “nonresponders” to treatment. We examined vertebral fracture (VF) risk, change in lumbar spine (LS) BMD, and change in amino‐terminal extension peptide of procollagen type I (PINP) in postmenopausal women whose femoral neck (FN) BMD decreased, increased, or was unchanged after receiving teriparatide (TPTD) or placebo (PL) in the Fracture Prevention Trial. FN and LS BMD were measured at baseline and 12 mo. VFs were assessed by lateral spine radiographs at baseline and study endpoint. A BMD change from baseline of >4% was considered to be clinically significant. Decreases of >4% FN BMD were less common in women receiving TPTD (10%) versus PL (16%, p < 0.05), yet women on TPTD who lost FN BMD still had significant reductions in VF risk compared with PL (RR = 0.11; 95% CI = 0.03–0.45). VF risk reduction with TPTD compared with PL was similar across categories of FN BMD change from baseline at 12 mo (loss >4%, loss 0–4%, gain 0–4%, or gain >4%; interaction p = 0.40). Irrespective of FN BMD loss or gain, TPTD‐treated women had statistically significant increases in LS BMD and PINP compared with PL. In both groups, losses or gains in FN BMD at 12 mo corresponded to losses or gains in BMC rather than changes in bone area. In conclusion, loss of FN BMD at 12 mo in postmenopausal women with osteoporosis treated with TPTD is nevertheless consistent with a good treatment response in terms of VF risk reduction.

Trabecular Bone Score in Patients With Chronic Glucocorticoid Therapy–Induced Osteoporosis Treated With Alendronate or Teriparatide

To determine the effect of alendronate (ALN) and teriparatide on trabecular bone score (TBS) in patients with glucocorticoid‐induced osteoporosis.

Assessing the Effects of Teriparatide Treatment on Bone Mineral Density, Bone Microarchitecture, and Bone Strength.

BACKGROUND To gain insight into how teriparatide affects various bone health parameters, we assessed the effects of teriparatide treatment with use of standard DXA (dual x-ray absorptiometry) technology and two newer technologies, high-resolution MRI (magnetic resonance imaging) and finite element analysis of quantitative CT (computed tomography) scans. METHODS In this phase-4, open-label study, postmenopausal women with severe osteoporosis received 20 μg/day of teriparatide. Assessments included (1) changes in areal BMD (bone mineral density) (in g/cm2) at the radius, spine, and hip on DXA, (2) changes in volumetric BMD (in mg/cm3) at the spine and hip on quantitative CT scans, (3) changes in bone microarchitecture at the radius on high-resolution MRI, (4) estimated changes in spine and hip strength according to finite element analysis of quantitative CT scans, (5) changes in bone turnover markers in serum, and (6) safety. RESULTS Thirty-five subjects were enrolled; thirty completed eighteen months and twenty-five completed an optional six-month extension. No significant changes were observed for the primary outcome, high-resolution MRI at the distal aspect of the radius. At month eighteen, the least-squares mean percentage change from baseline in total volumetric BMD at the spine was 10.05% (95% confidence interval [CI], 6.83% to 13.26%; p < 0.001), and estimated spine strength increased 17.43% (95% CI, 12.09% to 22.76%; p < 0.001). Total volumetric BMD at the hip increased 2.22% (95% CI, 0.37% to 4.06%; p = 0.021), and estimated hip strength increased 2.54% (95% CI, 0.06% to 5.01%; p = 0.045). Areal BMD increased at the lumbar spine and femoral neck, was unchanged for the total hip and at the distalmost aspect of the radius, and decreased at a point one-third of the distance between the wrist and elbow. Bone turnover markers increased at months three, six, and twenty-four (all p < 0.05). No unexpected adverse events were observed. CONCLUSIONS High-resolution MRI failed to identify changes in bone microarchitecture at the distal aspect of the radius, a non-weight-bearing site that may not be suitable for assessing effects of an osteoanabolic agent. Teriparatide increased areal BMD at the spine and femoral neck and volumetric BMD at the spine and hip. Estimated vertebral and femoral strength also increased. These findings and increases in bone turnover markers through month twenty-four are consistent with the known osteoanabolic effect of teriparatide. LEVEL OF EVIDENCE Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial.

AbstractBackground There is a medical need for therapies that improve hip fracture healing. Teriparatide (Forteo®/ Forsteo®, recombinant human parathyroid hormone) is a bone anabolic drug that is approved for treatment of osteoporosis and glucocorticoid-induced osteoporosis in men and postmenopausal women at high fracture risk. Preclinical and preliminary clinical data also suggest that teriparatide may enhance bone healing.Questions/purposesWe wished to test the hypotheses that treatment with teriparatide versus placebo would improve femoral neck fracture healing after internal fixation as measured by (1) frequency of revision surgery, (2) radiographic fracture healing, and (3) other outcomes including pain control, gait speed, and safety.MethodsWe initiated two separate, but identically designed, clinical trials to meet FDA requirements to provide substantial evidence to support approval of a new indication. The two prospective, randomized double-blind, placebo-controlled Phase III studies were designed to evaluate the effect of subcutaneous teriparatide (20 μg/day) for 6 months versus placebo on fracture healing at 24 months. The trials were conducted concurrently with a planned enrollment of 1220 patients per trial. However, enrollment was stopped owing to very slow patient accrual, and an a priori decision was made to pool the results of those studies for statistical analyses before study completion; pooling was specified in both protocols. Randomization was stratified by fixation (sliding hip screw or multiple cancellous screws) and fracture type (displaced or nondisplaced). An independent Central Adjudication Committee reviewed revision surgical procedures and radiographs. A total of 159 patients were randomized in the two trials (81 placebo, 78 teriparatide). The combined program had very low power to detect the originally expected treatment effect but had approximately 80% power to detect a larger difference of 12% between treatment groups for risk of revision surgery.ResultsThe proportion of patients undergoing revision surgery at 12 months was 14% (11 of 81) in the placebo group versus 17% (13 of 78) in the teriparatide group. Central Adjudication Committee review excluded two of these patients treated with placebo from the primary analysis. After exclusions, the proportion of patients who did not undergo revision surgery at 12 months (primary endpoint) was not different between the study and placebo groups, at 88% in the placebo group (90% CI, 0.79–0.93) versus 84% in the teriparatide group (90% CI, 0.75–0.90; p = 0.743). There also were no differences between groups in the proportion of patients achieving radiographic fracture healing at 12 months (75% [61 of 81] placebo versus 73% [57 of 78] teriparatide; odds ratio, 0.89; 90% CI, 0.46–1.72; p = 0.692) or in measures of pain control (such as pain during ambulation, 92% [55 of 62] placebo versus 91% [52 of 57] teriparatide; odds ratio, 0.91; 90% CI, 0.25–3.37; p = 0.681). The frequency of patients reporting adverse events was 49% [40 of 81] in the placebo group versus 45% [35 of 78] in the teriparatide group (p = 0.634) during the 6-month treatment period.ConclusionsThe small sample size limited this study’s power to detect potential differences, and the results are exploratory. With the patients available, teriparatide did not decrease the risk of revision surgery, improve radiographic signs of fracture healing, or decrease pain compared with the placebo. The adverse event data observed were consistent with the teriparatide safety profile. Functional and health outcome data from the studies may help improve our understanding of patients recovering from femoral neck fractures. Further large controlled studies are required to determine the effect of teriparatide on fracture healing.Level of EvidenceLevel II, prospective study.