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. INTRODUCTION: The effects of combining two approved treatments for osteoporosis with different modes of action were examined by comparing teriparatide [rhPTH(1-34)] monotherapy with combination teriparatide and raloxifene therapy. MATERIALS AND METHODS: A 6-month randomized, double-blind trial comparing teriparatide plus raloxifene (n = 69) versus teriparatide plus placebo (n = 68) was conducted in postmenopausal women with osteoporosis. RESULTS: Bone formation (N-terminal propeptide of type 1 collagen [PINP]) increased similarly in both treatment groups. However, the increase in bone resorption (serum C-terminal telopeptide of type I collagen [CTx]) in the combination group was significantly smaller than in the teriparatide-alone group (p = 0.015). Lumbar spine BMD significantly increased 5.19 +/- 0.67% from baseline in the teriparatide-alone group. In the combination group, lumbar spine (6.19 +/- 0.65%), femoral neck (2.23 +/- 0.64%), and total hip (2.31 +/- 0.56%) BMD significantly increased from baseline to study endpoint, and the increase in total hip BMD was significantly greater than in the teriparatide-alone group (p = 0.04). In the teriparatide-alone group, mean serum calcium levels increased from baseline to endpoint (0.30 +/- 0.06 mg/dl, p < 0.001), whereas mean serum phosphate remained unchanged. In the combination group, mean serum calcium was unchanged, and mean serum phosphate decreased (-0.20 +/- 0.06 mg/dl, p < 0.001) from baseline to endpoint. Changes in serum calcium (p < 0.001) and phosphate (p < 0.004) were significantly different between treatment groups. The safety profile of combination therapy was similar to teriparatide alone. CONCLUSIONS: Combination therapy increased bone formation to a similar degree as teriparatide alone. However, the increase in bone resorption was significantly less and total hip BMD significantly increased for combination therapy compared with teriparatide alone. Combination treatment with raloxifene may thus enhance the bone forming effects of teriparatide. Further studies over longer treatment duration that include fracture endpoints are necessary to fully ascertain the clinical significance of combination raloxifene plus teriparatide therapy in postmenopausal osteoporosis.     

Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis

Clinical data suggest concomitant therapy with bisphosphonates and parathyroid hormone (PTH) may blunt the anabolic effect of PTH; rodent models suggest that infrequently administered bisphosphonates may interact differently. To evaluate the effects of combination therapy with an intravenous infusion of zoledronic acid 5 mg and daily subcutaneous recombinant human (rh)PTH(1–34) (teriparatide) 20 µg versus either agent alone on bone mineral density (BMD) and bone turnover markers, we conducted a 1‐year multicenter, multinational, randomized, partial double‐blinded, controlled trial. 412 postmenopausal women with osteoporosis (mean age 65 ± 9 years) were randomized to a single infusion of zoledronic acid 5 mg plus daily subcutaneous teriparatide 20 µg (n = 137), zoledronic acid alone (n = 137), or teriparatide alone (n = 138). The primary endpoint was percentage increase in lumbar spine BMD (assessed by dual‐energy X‐ray absorptiometry [DXA]) at 52 weeks versus baseline. Secondary endpoints included change in BMD at the spine at earlier time points and at the total hip, trochanter, and femoral neck at all time points. At week 52, lumbar spine BMD had increased 7.5%, 7.0%, and 4.4% in the combination, teriparatide, and zoledronic acid groups, respectively (p < .001 for combination and teriparatide versus zoledronic acid). In the combination group, spine BMD increased more rapidly than with either agent alone (p < .001 versus both teriparatide and zoledronic acid at 13 and 26 weeks). Combination therapy increased total‐hip BMD more than teriparatide alone at all times (all p < .01) and more than zoledronic acid at 13 weeks (p < .05), with final 52‐week increments of 2.3%, 1.1%, and 2.2% in the combination, teriparatide, and zoledronic acid groups, respectively. With combination therapy, bone formation (assessed by serum N‐terminal propeptide of type I collagen [PINP]) increased from 0 to 4 weeks, declined minimally from 4 to 8 weeks, and then rose throughout the trial, with levels above baseline from 6 to 12 months. Bone resorption (assessed by serum β‐C‐telopeptide of type I collagen [β‐CTX]) was markedly reduced with combination therapy from 0 to 8 weeks (a reduction of similar magnitude to that seen with zoledronic acid alone), followed by a gradual increase after week 8, with levels remaining above baseline for the latter half of the year. Levels for both markers were significantly lower with combination therapy versus teriparatide alone (p < .002). Limitations of the study included its short duration, lack of endpoints beyond DXA‐based BMD (e.g., quantitative computed tomography and finite‐element modeling for bone strength), lack of teriparatide placebo, and insufficient power for fracture outcomes. We conclude that while teriparatide increases spine BMD more than zoledronic acid and zoledronic acid increases hip BMD more than teriparatide, combination therapy provides the largest, most rapid increments when both spine and hip sites are considered. © 2011 American Society for Bone and Mineral Research.     

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.     

Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate.

We investigated the effects of 18 months of treatment with teriparatide in patients previously treated with long-term antiresorptive therapy using bone turnover markers and bone densitometry. Previous raloxifene treatment allowed for teriparatide-induced early bone marker and BMD increases comparable with previously published results for treatment-n?ive patients. Conversely, previous alendronate treatment reduced the bone marker and BMD response. INTRODUCTION: Teriparatide [rhPTH(1-34)] has been shown to increase BMD and reduce the risk of fracture in postmenopausal women with osteoporosis. Our objective was to investigate the skeletal effects of 18 months of treatment with teriparatide in women whose osteoporosis was previously treated with either alendronate or raloxifene. MATERIALS AND METHODS: Daily subcutaneous injections of 20 microg teriparatide were administered for 18 months to 59 postmenopausal women, 60-87 years of age, with BMD T-scores 相似文献   

Effects of morning vs. evening teriparatide injection on bone mineral density and bone turnover markers in postmenopausal osteoporosis

Summary

A 12-month morning teriparatide (TPTD) administration resulted in a larger increase in the lumbar spine bone mineral density (BMD) than the evening application. The results indicate that the response of bone cells to teriparatide treatment depends on dosing time.

Introduction

The aim of this study was to assess the long-term effects of the morning vs. the evening teriparatide administration on BMD and bone turnover markers (BTMs) in postmenopausal osteoporosis.

Methods

Fifty women with established postmenopausal osteoporosis were randomized to 12-month treatment with 20?μg of TPTD, administered daily in the morning or in the evening. The BMD and serum concentrations of C-terminal telopeptide of type I collagen, N-terminal propeptide of type I procollagen (PINP), and tartrate-resistant acid phosphatase isoform 5b (TRAP 5b) were measured at baseline, after 6 and 12?months. General linear model-repeated measurements were used to analyze the data.

Results

After 12?months, the lumbar spine BMD grew markedly (p?<?0.001) with a significantly greater increase in the morning arm compared to the evening arm (9.1% vs. 4.8%, respectively, p?<?0.05). The BMD at the distal radius significantly decreased (p?<?0.001), with no differences between the arms. The BMD at proximal femur did not change significantly. After 6 months, the BTMs were significantly increased compared with baseline (p?<?0.001). The increases in the evening arm vs. the morning arm, however, were more pronounced in PINP (+358% vs. +215%, respectively) and in TRAP 5b (+70% vs. +37%, respectively) (both p?<?0.05).

Conclusion

12-month morning administration of TPTD resulted in a larger increase in the lumbar spine BMD than the evening application. The timing of TPTD administration may be important for its efficacy.     

Bone stock reconstruction for huge bone loss using allograft-bones,bone marrow,and teriparatide in an infected total knee arthroplasty

Bone stock reconstruction using allograft-bones, bone marrow (BM), and teriparatide (TPTD) is reported. Huge and extensive bone losses occurred in the medullary cavity of the femur and tibia of a 55-year-old female rheumatoid arthritis patient with severe osteoporosis after debridement of her infected total knee arthroplasty. Because of the risks of unstable prosthetic fixation and intra-operation fracture, we first reconstructed the bone stock. Chipped allograft bones mixed with BM were implanted in the bone defects, and TPTD was administrated for the osteoporosis therapy. Good bone formation was found by computed tomography after 4 months. Bone turnover markers and bone mineral density (BMD) were increased at 6 months. We confirmed good bone formation at the re-implantation surgery. The newly formed bone harvested during the re-implantation surgery showed active osteoblast-like lining cells. TPTD is known to enhance allograft bone union, mesenchymal stem cell differentiation into osteoblasts, and BMD. This tissue engineering-based technique might be improved by the various effects of TPTD. This method without any laboratory cell culture might be a good option for bone stock reconstruction surgery in ordinary hospitals.     

Antiresorptives overlapping ongoing teriparatide treatment result in additional increases in bone mineral density

During teriparatide (TPTD) treatment, high levels of bone formation are accompanied by an increase in bone resorption. The aim of this work was to test if coadministration of raloxifene (RAL) or alendronate (ALN) following 9 months of ongoing TPTD therapy would reopen the anabolic window, thereby exerting additional benefit on bone mineral density (BMD). Postmenopausal women (n = 125) with severe osteoporosis on TPTD treatment for 9 months were randomized into three open‐label groups for a further 9 months: ALN (70 mg/week) in addition to TPTD; RAL (60 mg/d) in addition to TPTD; or no medication in addition to TPTD. Amino‐terminal propeptide of type I procollagen (P1NP) and cross‐linked C‐telopeptide (CTX), and areal and volumetric BMD at the lumbar spine and hip were assessed. During the combination period, P1NP concentrations did not change on TPTD monotherapy (693% ± 371%, p < 0.0001) and decreased in the ALN (360% ± 153%, p < 0.0001) and RAL (482% ± 243%, p < 0.0001) combination groups; whereas CTX did not change on TPTD monotherapy (283% ± 215%, p < 0.0001), decreased to the starting level in the ALN combination group (17% ± 72%, p = 0.39), and remained elevated in the RAL combination group (179% ± 341%, p < 0.0001). The increase in lumbar spine BMD was 5% ± 6.3% in the ALN and 6% ± 5.2% in the RAL combination groups compared with 2.8% ± 9.3% in the TPTD monotherapy group (p = 0.085 and p = 0.033, respectively). The increase of trabecular lumbar spine BMD for both the ALN and RAL combination groups was superior to TPTD monotherapy. Total hip BMD changes were 4% ± 5.3% for the ALN combination group and 1.4% ± 5.1% for the TPTD monotherapy (p = 0.032), and 1.4% ± 3.4% (p = 0.02) for the RAL combination group. With the exception of no differences in the trabecular compartment of femoral neck, volumetric BMD changes in the ALN combination group for all other comparisons were significantly superior to the two other groups. Our data suggest that ALN when added to TPTD 9 months after initiation of TPTD monotherapy results in a more robust increase in BMD, probably due to a reopening of the anabolic window. The clinical relevance of the BMD increase is unknown. © 2013 American Society for Bone and Mineral Research     

Prevention and treatment of osteoporosis: efficacy of combination of hormone replacement therapy with other antiresorptive agents.

Osteoporosis is a debilitating disease characterized by decreased bone mineral density (BMD) leading to fractures. It primarily affects postmenopausal women and elderly men. Prevention of osteoporosis is very important because present therapies do not have the potential to mend damage to the bone microarchitecture caused by osteoporosis. The first line of prevention and treatment of osteoporosis is hormone replacement therapy (HRT). All of the approved drugs for the prevention and treatment of osteoporosis act as inhibitors of bone resorption; these drugs include HRT, selective estrogen receptor modulators, calcitonin, and bisphosphonates. The latter two drugs have also been shown to prevent fractures. This article discusses data from nine controlled prospective clinical studies. Study 1 was designed to assess the efficacy of combined HRT and bisphosphonate in preventing osteoporosis during the early stages of menopause. This combined therapy increased the lumbar spine BMD by 10.9% and femoral BMD by 7.3% over 4 yr, compared with 6.8 and 4.0% with HRT alone, and 6.8 and 1.2% with bisphosphonate alone. Study 2 was conducted on postmenopausal women with established osteoporosis. These results showed a 10.4 and 7.0% increase in BMD in vertebrae and femora, respectively, compared with 7.3 and 4.8% increases in the HRT group, and 6.8 and 0.9% in the bisphosphonate group. Data from study 3 demonstrated similar findings in that the combination of alendronate and HRT also enhanced BMD values. Studies 4 and 5 assessed the efficacy of the combined therapy of HRT and calcitonin in the prevention of early postmenopausal bone loss. Both studies demonstrated a significant increase in BMD over and above that observed with either HRT or calcitonin alone. Studies 6, 7, and 8 demonstrated that the addition of testosterone to estrogen therapy further increased BMD when compared to estrogen therapy alone, and also prevented the expected decreases in markers of bone formation in early postmenopausal women. Study 9 demonstrated a synergistic effect on BMD in postmenopausal women, when HRT was coadministered with monofluorophosphate. Other combination therapies may also enhance BMD (e.g., the combination of alendronate and parathyroid hormone [PTH]). However, some agents either lose their efficacy or have no added effects on BMD when they are coadministered (e.g., tiludronate and PTH, calcitonin and PTH, calcitonin and anabolic steroids). These studies illustrate that in a subgroup of patients (i.e., patients with high bone turnover and/or severe osteoporosis), specific combination treatments such as HRT with bis-phosphonates, calcitonin, or androgens (and perhaps also with PTH, fluoride, nitric oxide donors) provide additional beneficial effects over a single-drug therapy. Whether these combination therapies are more effective than individual drugs in reducing fractures still needs to be determined.     

Reduction in vertebral fracture risk in teriparatide-treated postmenopausal women as assessed by spinal deformity index

Teriparatide is the first bone-building drug available for the treatment of osteoporosis. We investigated the efficacy of this compound as assessed by spinal deformity index (SDI) using data from the Fracture Prevention Trial (FPT). The FPT was a randomized, double blind trial of placebo versus teriparatide 20 microg (TPTD20) versus teriparatide 40 microg (TPTD40) administered by daily self-injection. Patients included in the current analyses were those patients from the placebo (n = 398) and TPTD20 (the approved dose, n = 403) groups with baseline and follow-up radiographs and at least one vertebral fracture at baseline. For each vertebra, a visual semiquantitative grade of 0, 1, 2, or 3 was assigned for no fracture or mild, moderate, or severe fracture, respectively; the SDI was calculated by summing the fracture grades of all T4 to L4 vertebrae. The mean SDI increased in the placebo and TPTD20 groups by 0.485 and 0.134, respectively (P < 0.001). The proportions of patients with SDI increases >1, >2, and >3 were reduced by 85%, 80%, and 80%, respectively. In the placebo group, increasing baseline SDI was correlated with the mean increase in SDI during the trial (r = 0.080, P = 0.01), consistent with the progressive natural history of osteoporosis. However, in the TPTD20 group, increasing baseline SDI was not correlated with the mean increase in SDI during the trial (P = 0.297) indicating that teriparatide mitigated or eliminated the increased risk associated with increasing fracture burden. Increases in SDI during the trial were associated with increasing proportions of patients with new or worsening back pain and greater mean height loss (P < 0.0001), demonstrating an association with important clinical consequences. The results indicate that teriparatide greatly reduced the increase in fracture burden in the FPT and mitigated or eliminated the risk for future fractures imparted by increasing baseline fracture burden.     

Retreatment With Teriparatide One Year After the First Teriparatide Course in Patients on Continued Long‐Term Alendronate

Patients treated with teriparatide after prior and ongoing alendronate therapy experience spine BMD increases; however, some continue to be at high risk for fracture, based on persistently low BMD and/or fracture history. The objective of this study was to determine whether a second discrete retreatment course with teriparatide could produce similar biochemical and BMD changes as seen during the first teriparatide course. In the original treatment study, 126 women on alendronate for ≥1 yr were randomized to continue alendronate and receive daily teriparatide, cyclic teriparatide (3‐mo cycles), or alendronate alone for 15 mo. Of the 72 patients who completed either original teriparatide regimen, 49 completed a 12‐mo follow‐up on continued alendronate alone. At that time, 32 patients, who remained at high risk of future fracture, were recruited into the retreatment protocol and 27 completed another course of teriparatide administered daily for 15 mo (including 15 from the original daily treatment group and 12 from the original cyclic treatment group). Bone formation indices (propeptide of type I procollagen and osteocalcin) increased during both teriparatide courses with median 3‐mo increments of 120% and 72% above baseline during the original course and 60% and 40% above baseline during retreatment, respectively. Mean spine BMD increments were 6.2% after the first daily course and 4.7% after retreatment and 4.1% after the first course of cyclic teriparatide and 4.9% after retreatment. We conclude that retreatment with teriparatide stimulates bone formation and increases spine BMD to a similar extent as seen during the original teriparatide course. Retreatment with teriparatide may be a viable option for some patients with severe osteoporosis who have received prior teriparatide therapy.     

Treatment Sequence Matters: Anabolic and Antiresorptive Therapy for Osteoporosis

The effects of anabolic medications (teriparatide [TPTD] and parathyroid hormone [PTH]) differ in patients who have received recent treatment with potent antiresorptives. This perspective reviews studies evaluating bone density (BMD) and histomorphometric effects of treatment sequences beginning with TPTD/PTH followed by potent antiresorptives and those beginning with potent antiresorptives followed by switching to or adding TPTD. Effect of treatment sequence on spine BMD outcome is minor, with modest quantitative differences. However, when individuals established on potent bisphosphonates are switched to TPTD, hip BMD declines below baseline for at least the first 12 months after the switch to TPTD. This transient hip BMD loss is more prominent when the antiresorptive is denosumab; in this setting, hip BMD remains below baseline for almost a full 24 months. In a controlled comparison of those who switched from alendronate to TPTD versus those who added TPTD to ongoing alendronate, the effect on hip BMD was improved with combination therapy. Furthermore, hip strength improved with the addition of TPTD to ongoing alendronate, whereas it was neutral after switching from alendronate to TPTD, primarily due to the effect on cortical bone. Bone biopsy studies indicate that TPTD stimulates bone formation in patients who have not been treated previously as well as in patients on prior and ongoing bisphosphonates. Histomorphometric evidence suggests that use of alendronate with TPTD blocks the TPTD‐induced increase in cortical porosity. When possible, we suggest anabolic therapy first, followed by potent antiresorptive therapy. The common practice of switching to TPTD only after patients have an inadequate response to antiresorptives (intercurrent fracture or inadequate BMD effect) is not the optimal utilization of anabolic treatment. In fact, this may result in transient loss of hip BMD and strength. In this setting, continuing a potent antiresorptive while starting TPTD might improve hip outcomes. © 2017 American Society for Bone and Mineral Research.     

Effects of combined teriparatide and zoledronic acid on posterior lumbar vertebral fusion in an aged ovariectomized rat model of osteopenia

There has been no study regarding the effect of a combination of teriparatide (TPTD) and zoledronic acid (ZA) on vertebral fusion. In this study, we investigate the effect of single and combined TPTD and ZA treatment on lumbar vertebral fusion in aged ovariectomized (OVX) rats. Sixty two‐month‐old female Sprague‐Dawley rats were ovariectomized and underwent bilateral L4–L5 posterolateral intertransverse fusion after 10 months. The OVX rats received vehicle (control) treatment, or ZA (100 µg/kg, once), or TPTD (60 µg/kg/2 d for 42 d), or ZA + TPTD until they were euthanized at 6 weeks following lumbar vertebral fusion. The lumbar spine was harvested. Bone mineral density (BMD), bone fusion, bone volume (BV), and bone formation rate (BFR)were analyzed by dual‐energy X‐ray absorptiometry (DXA), radiography, micro‐computed tomography, and histomorphometry. Compared with vehicle (control) treatment, ZA and TPTD monotherapy increased bone volume (BV) at fusion site, and ZA + TPTD combined therapy had an additive effect. Treatment with TPTD and ZA + TPTD increased the bone fusion rate when compared with the control group. ZA monotherapy did not alter the rate of bone fusion. The TPTD and ZA + TPTD treatment groups had increased mineral apposition rate (MAR), mineralizing surfaces/bone surface ((MS/BS), and BFR/BS compared with the OVX group. Our experiment confirm that the monotherapy with TPTD and combination therapy with ZA + TPTD in an OVX rat model of osteopenia following lumbar vertebral fusion surgery increased bone fusion mass and bone fusion rate, and ZA + TPTD combined therapy had an additive effect on bone fusion mass. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:937–944, 2018.

     

Differential Effects of Teriparatide and Zoledronic Acid on Bone Mineralization Density Distribution at 6 and 24 Months in the SHOTZ Study

The Skeletal Histomorphometry in Patients on Teriparatide or Zoledronic Acid Therapy (SHOTZ) study assessed the progressive effects of teriparatide (TPTD) and zoledronic acid (ZOL) on bone remodeling and material properties in postmenopausal women with osteoporosis. Previously, we reported that biochemical and histomorphometric bone formation indices were significantly higher in patients receiving TPTD versus ZOL. Here we report bone mineralization density distribution (BMDD) results based on quantitative backscattered electron imaging (qBEI). The 12‐month primary study was randomized and double blind until the month 6 biopsy, then open label. Patients (TPTD, n = 28; ZOL, n = 31) were then eligible to enter a 12‐month open‐label extension with their original treatment: TPTD 20 μg/d (subcutaneous injection) or ZOL 5 mg/yr (intravenous infusion). A second biopsy was collected from the contralateral side at month 24 (TPTD, n = 10; ZOL, n = 10). In cancellous bone, ZOL treatment was associated at 6 and 24 months with significantly higher average degree of mineralization (Ca_MEAN, +2.2%, p = 0.018; +3.9%, p = 0.009, respectively) and with lower percentage of low mineralized areas (Ca_LOW, –34.6%, p = 0.029; –33.7%, p = 0.025, respectively) and heterogeneity of mineralization Ca_WIDTH (–12.3%, p = 0.003; –9.9%, p = 0.012, respectively), indicating higher mineralization density and more homogeneous mineral content versus TPTD. Within the ZOL group, significant changes were found in all parameters from month 6 to 24, indicating a progressive increase in mineralization density. In sharp contrast, mineralization density did not increase over time with TPTD, reflecting ongoing deposition of new bone. Similar results were observed in cortical bone. In this study, TPTD stimulated new bone formation, producing a mineralized bone matrix that remained relatively heterogeneous with a stable mean mineral content. ZOL slowed bone turnover and prolonged secondary mineralization, producing a progressively more homogeneous and highly mineralized bone matrix. Although both TPTD and ZOL increase clinical measures of bone mineral density (BMD), this study shows that the underlying mechanisms of the BMD increases are fundamentally different. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).     

Effects of Denosumab and Teriparatide Transitions on Bone Microarchitecture and Estimated Strength: the DATA‐Switch HR‐pQCT study

In postmenopausal osteoporosis, switching from teriparatide to denosumab results in continued bone mineral density (BMD) gains whereas switching from denosumab to teriparatide results in BMD loss. To assess the effects of these transitions on bone microarchitecture and strength, we performed high‐resolution peripheral QCT (HR‐pQCT) at the distal tibia and radius in postmenopausal osteoporotic women who received 24 months of teriparatide 20 μg daily followed by 24 months of denosumab 60 mg every 6 months, 24 months of denosumab followed by 24 months of teriparatide, or 24 months of both medications followed by 24 months of denosumab. The 77 women who completed at least one post‐switch visit are included in this analysis. Tibial cortical volumetric BMD (vBMD) increased between months 24 and 48 in the teriparatide‐to‐denosumab (net 48‐month change –0.8% ± 2.4%) and combination‐to‐denosumab groups (net 48‐month changes +2.4% ± 4.1%) but decreased in the denosumab‐to‐teriparatide group (net 48‐month change –3.4% ± 3.2%, p < 0.001 for all between‐group comparisons). Changes in total vBMD, cortical thickness, and estimated stiffness (by micro–finite element analysis [µFEA]) followed a similar pattern, as did changes at the radius. Conversely, tibial cortical porosity remained stable between months 24 and 48 in the teriparatide‐to‐denosumab and combination‐to‐denosumab groups (net 48‐month changes +7.2% ± 14.8% and –3.4% ± 12.1%, respectively) but increased in the denosumab‐to‐teriparatide group (net 48‐month change +16.2% ± 11.5%, p < 0.05 versus other groups). Trabecular vBMD changes did not differ among groups. Together, these findings demonstrate that in women treated with denosumab, switching to teriparatide is associated with a reduction in total and cortical vBMD, cortical thickness, and estimated strength, whereas switching to denosumab from teriparatide or combination therapy results in improvements in these parameters with the greatest improvements observed in women treated with combined therapy followed by denosumab. These findings strongly suggest that the use of teriparatide after denosumab should be avoided and that the use of combined teriparatide/denosumab followed by denosumab alone may be a useful treatment strategy in those with severe osteoporosis. © 2017 American Society for Bone and Mineral Research.     

Overlapping and Continued Alendronate or Raloxifene Administration in Patients on Teriparatide: Effects on Areal and Volumetric Bone Mineral Density—The CONFORS Study

Nine month teriparatide (TPTD) monotherapy followed by co‐administration of raloxifene (RAL) or alendronate (ALN) for another nine 9 months resulted in incremental bone mineral density (BMD) increase. The aim of this study was to investigate the effects of continued antiresorptive treatments for 12 months in the extension phase. Postmenopausal women (n = 125) with severe osteoporosis on ongoing TPTD treatment for 9 months were randomized into three open‐label groups for another 9 months: ALN (70 mg/week, n = 41), RAL (60 mg/d, n = 37) in addition to TPTD or no additional medication (n = 47) except Ca and vitamin D. After discontinuation of TPTD the respective antiresorptives were continued for a further 12 months, while patients in the TPTD monotherapy group received Ca and vitamin D. Amino‐terminal propeptide of type I procollagen (P1NP) and cross‐linked C‐telopeptide (CTX), areal and volumetric BMD at the lumbar spine (LS) and hip were assessed. ALN resulted in continued BMD increase in LS (4.3 ± 1.5%; mean ± SD), femoral neck (4.2 ± 1.6%) and total hip (4 ± 1.6%; p < 0.001 for all), while RAL was only effective at the LS (2.4 ± 1.7%, p < 0.001) but no changes at the femoral neck (0.4 ± 1.4%) or total hip (?0.8 ± 1.5%) were observed. Cortical bone only increased in the ALN group (femoral neck 6.7 ± 2.7% and ?1.3 ± 2.5%; total hip 13.8 ± 2.9% and ?2.3 ± 2.5% for ALN and RAL, p < 0.001 for all; respectively). Analyzing the entire 30 months of therapy, the ALN group revealed the largest BMD increase in all regions. Our results suggest that the addition of ALN to ongoing TPTD and continuing ALN after TPTD was stopped may be beneficial for patients in terms of areal and volumetric BMD increase. Further research is warranted to determine the optimal timing of the initiation of the combination treatment, the respective antiresorptive medication and the potential benefit of this BMD increase regarding fracture prevention. © 2014 American Society for Bone and Mineral Research     

Effects of teriparatide [rhPTH (1-34)] treatment on structural geometry of the proximal femur in elderly osteoporotic women

Introduction: We evaluated effects of teriparatide (rDNA origin) injection [teriparatide, rhPTH (1–34), TPTD] on hip structure among a subset 558 postmenopausal women enrolled in the Fracture Prevention Trial. Methods: Patients were randomized to once-daily, self-administered subcutaneous injections of placebo (N = 189), teriparatide 20 μg (TPTD20; N = 186), or 40 μg (TPTD40; N = 183) for a median of 20 months. Repeated dual energy X-ray absorptiometry (DXA) hip scans were analyzed with the Hip Structure Analysis (HSA) program to derive structural geometry. Results and conclusions: There were no significant differences in age or body size between groups at baseline, 1 year, or study termination. At the femoral neck, teriparatide increased bone mass and improved bone geometric strength in both treatment groups compared to the placebo group, with the response being dose-related. The mean difference (95% CI) in bone cross-sectional area (CSA) in the TPTD20 was 3.5% (1.8% to 5.3%), and 6.3% (4.5% to 8.2%) in TPTD40 at study termination, compared to placebo controls. Teriparatide treatment increased bending strength, with the mean difference in section modulus being 3.6% (1.4% to 5.8%) and 6.8% (4.6% to 9.1%) greater in the TPTD20 and TPTD40 groups, respectively. Compared to placebo, local cortical instability characterized by the buckling ratio decreased by 5.5% (3.5% to 7.5%) and 8.6% (6.6% to 10.5%) in the TPTD20 and TPTD40 groups, respectively, during the study period. The changes at the intertrochanteric region were comparable to those at the narrow neck although between-group differences were slightly smaller. Except for an inconsequential (1%) improvement in section modulus in TPTD20, teriparatide effects did not reach significance at the femoral shaft. In conclusion, teriparatide treatment improved axial and bending strength, and increased cortical thickness and stability at the femoral neck and intertrochanteric region. Teriparatide treatment effects were not apparent at the purely cortical femoral shaft.     

Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal.

Our best pharmacologic agents for osteoporosis treatment prevent no more than 40-60% of osteoporotic fractures in patients at highest risk. Thus, there is a need for agents that can further augment bone mass and reduce fracture risk more substantially. To this end, we investigated the utility of parathyroid hormone (PTH) in combination with established hormone-replacement therapy (HRT) in women with osteoporosis. Fifty-two women who had been on HRT for at least 2 years were enrolled in this trial in which 25 were assigned randomly to remain on HRT alone and 27 were assigned to remain on HRT and also receive daily subcutaneous PTH(1-34) 400 U (25 microg) per day for 3 years. Bone mineral density (BMD) measurements at the spine, hip, and total body as well as biochemical determinations of bone turnover and calcium homeostasis were obtained every 6 months. Lateral thoracic and lumbar spine X-rays were obtained at baseline and annually. Subjects also had measurements of bone density and biochemical indices of bone turnover 1 year after discontinuation of PTH, while HRT was continued. In the group receiving HRT alone, bone density and biochemical variables of bone turnover remained stable throughout the 3-year treatment trial and 1-year follow-up. In the PTH + HRT group, biochemical variables of bone formation and resorption peaked at 6 months and subsequently remained elevated until 30 months at which time levels were indistinguishable from baseline. Subjects in the PTH + HRT group increased bone mass by 13.4+/-1.4% in the spine, 4.4+/-1.0% in the total hip, and 3.7+/-1.4% in the total body. Bone density measurements remained stable 1 year after discontinuation of PTH without any significant loss while women continued HRT. Biochemical variables did not change significantly after cessation of PTH through the 1-year follow-up period. PTH + HRT reduced the percent of women who had vertebral fractures from 37.5% to 8.3% (using a 15% height reduction criterion) and from 25% to 0% (using a 20% height reduction criterion) compared with women receiving HRT alone (p < 0.02 for both). We conclude that ongoing HRT maintains almost all of the PTH-induced bone mass increment for 1 year after discontinuation of PTH. Furthermore, PTH in combination with hormone therapy is an effective means of increasing bone mass throughout the skeleton and specifically reducing vertebral fracture occurrence by 75-100%, compared with HRT alone.     

Anabolic and Antiresorptive Therapy for Osteoporosis: Combination and Sequential Approaches

In the recent Bone Key Reports review, it was noted that combinations of anabolic and antiresorptive agents have potential to improve bone density and bone strength more than either agent as monotherapy. Small clinical trials have been performed evaluating combinations of PTH1-34 (TPTD) or PTH1-84 (PTH) with a variety of antiresorptives including hormone/estrogen therapy, raloxifene, alendronate, risedronate, ibandronate, zoledronic acid, and denosumab. Most of the studies evaluate dual-energy X-ray absorptiometry outcomes, and a few trials report volumetric mineral density (BMD) by quantitative computed tomography, followed by finite element modeling to calculate bone strength. None of the studies has been powered to assess differences in fracture incidence between combination therapy and monotherapy. BMD outcomes vary based on the timing of introduction of the anabolic agent (before, during, or after antiresorptive treatment), as well as the specific anabolic and antiresorptive used. Furthermore, effects of combination therapies are site-dependent. The most consistent effect of combining antiresorptive agents with PTH or TPTD is a superior hip BMD outcome compared with TPTD/PTH alone. This is most evident when TPTD/PTH is combined with a bisphosphonate or denosumab. In contrast to findings in the hip, in the majority of studies, there is no benefit to spine BMD with combination therapy vs monotherapy. The 2 exceptions to this are when TPTD is combined with denosumab and when TPTD is given as monotherapy first for 9 months, followed by the addition of alendronate (with continuation administration of TPTD). Based on what we now know, in patients previously treated with bisphosphonates who suffer hip fractures or who have very low or declining hip BMD, strong consideration should be given to starting TPTD and continuing a potent antiresorptive agent (possibly switching to zoledronic acid or denosumab) to improve hip BMD and strength quickly. Furthermore, in treatment naïve individuals with very severe osteoporosis, such as those with spine and hip fractures, combination therapy with TPTD and denosumab or TPTD followed by combination treatment with a potent bisphosphonate or denosumab should be considered to maximize early increases in BMD throughout the skeleton (Cosman BoneKEy Rep 3, 2014)[1].     

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.     

Monitoring teriparatide-associated changes in vertebral microstructure by high-resolution CT in vivo: results from the EUROFORS study.

We introduce a method for microstructural analysis of vertebral trabecular bone in vivo based on HRCT. When applied to monitor teriparatide treatment, changes in structural variables exceeded and were partially independent of changes in volumetric BMD. INTRODUCTION: Monitoring of osteoporosis therapy based solely on bone densitometry is insufficient to assess anti-fracture efficacy. Assessing bone microstructure in vivo is therefore of importance. We studied whether it is possible to monitor effects of teriparatide on vertebral trabecular microstructure independent of BMD by high-resolution CT (HRCT). MATERIALS AND METHODS: In a subset of 65 postmenopausal women with established osteoporosis who participated in the EUROFORS study, HRCT scans of T(12), quantitative CT of L(1)-L(3), and DXA of L(1)-L(4) were performed after 0, 6, and 12 mo of teriparatide treatment (20 microg/d). We compared BMD and 3D microstructural variables in three groups of women, based on prior antiresorptive treatment: treatment-na?ve; pretreated; and pretreated women showing inadequate response to treatment. RESULTS: We found statistically highly significant increases in most microstructural variables and BMD 6 mo after starting teriparatide. After 12 mo, apparent bone volume fraction (app. BV/TV) increased by 30.6 +/- 4.4% (SE), and apparent trabecular number (app. Tb.N.) increased by 19.0 +/- 3.2% compared with 6.4 +/- 0.7% for areal and 19.3 +/- 2.6% for volumetric BMD. The structural changes were partially independent of BMD as shown by a significantly larger standardized increase and a standardized long-term precision at least as good as DXA. Patients who had shown inadequate response to prior osteoporosis treatment did show improvements in BMD and structural measures comparable to treatment-na?ve patients. CONCLUSIONS: HRCT is a feasible method for longitudinal microstructural analysis of human vertebrae in vivo, offers information beyond BMD, and is sufficiently precise to show profound effects of teriparatide after 12 mo.