Efficacy and safety of denosumab and teriparatide versus oral bisphosphonates to treat postmenopausal osteoporosis: a systematic review and meta-analysis.

Study Design: A systematic review and Meta-analysis. Objective: To compare the efficacy and safety of denosumab and teriparatide versus oral bisphosphonates to treat postmenopausal osteoporosis. Summary of Background Data: While bisphosphonates have historically been the cornerstone of pharmacological management for bone protection in patients, emerging evidence suggests that teriparatide and denosumab warrant further investigation as potential first-line treatments. The optimal choice among denosumab, teriparatide, and oral bisphosphonates for the treatment of postmenopausal osteoporosis remains a subject of ongoing debate and controversy within the scientific community. Methods: This systematic review adhered meticulously to the rigorous standards outlined by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines as well as the Cochrane Collaboration recommendations. Additionally, it employed the AMSTAR (Assessing the methodological quality of systematic reviews) criteria to ensure methodological robustness and enhance the credibility of the findings. A systematic electronic search was conducted across Web of Science, PubMed, and the Cochrane Library databases from their inception dates up to February 2024. Results: In this meta-analysis of studies, our findings suggest that compared to bisphosphonates, both teriparatide and denosumab demonstrated notable increases in percentage changes in lumbar spine bone mineral density (BMD) among postmenopausal osteoporosis patients. Furthermore, denosumab exhibited superiority over teriparatide and oral bisphosphonates in enhancing percentage changes in both femoral neck and total hip BMD, indicating its potential as a more efficacious option. Regarding safety outcomes, no significant differences were observed in the incidence of serious adverse events among patients treated with teriparatide, denosumab, and bisphosphonates. However, teriparatide showed superiority over oral bisphosphonates in terms of a lower risk of general adverse events, suggesting a favorable safety profile. Conclusion: In conclusion, our study suggests that teriparatide and denosumab demonstrate comparable or potentially superior efficacy and safety profiles compared to oral bisphosphonates for the treatment of postmenopausal osteoporosis. Systematic Review Registration: PROSPERO, identifier CRD42024508382.

Effects of differences in dose and frequency of teriparatide on bone structure in Proximal Femur. - Analysis by DXA-based 3D-modeling (3D-SHAPER Software) -TRIPLE-BONE study (The effects of TeRIParatide preparation on bone mineraL density increase and BONE structure).

Trends toward more favorable improvement of the cortical bone parameters by once-weekly (56.5 µg once a week) and twice-weekly teriparatide (28.2 µg twice a week), and that of the trabecular bone parameters by once-daily (1/D) teriparatide (20 µg/day once a day) were shown. PURPOSE: To examine the effects of differences in the amount of teriparatide (TPTD) per administration and its dosing frequency on the bone structure in the proximal femur by dual-energy X-ray absorptiometry (DXA)-based 3D-modeling (3D-SHAPER software). METHODS: This was a multicenter retrospective study. Patients aged 50 years or older with primary osteoporosis who continuously received once-/twice-weekly (1・2/W, n = 60) or 1/D TPTD (n = 14) administration for at least one year were included in the study. Measurement regions included the femoral neck (FN), trochanter (TR), femoral shaft (FS), and total proximal hip (TH). Concurrently, the bone mineral density (BMD) and Trabecular Bone Score (TBS) were measured. RESULTS: The cross-sectional area, cross-sectional moment of inertia, and section modulus in the FS were significantly improved in the 1・2/W TPTD group, as compared to the 1/D TPTD group. However, significant improvement of the cortical thickness and buckling ratio in the FN was observed in the 1/D TPTD group, as compared to the 1・2/W TPTD group. Trabecular BMD values in the FS and TH were significantly increased in the 1/D TPTD group, as compared to the 1・2/W TPTD group, while the cortical BMD values in the TR, FS, and TH were significantly increased in the 1・2/W TPTD group, as compared to the 1/D TPTD group. CONCLUSION: Trends toward more favorable improvement of the cortical bone by 1・2/W TPTD and that of the trabecular bones by 1/D TPTD were observed.

Effects of daily teriparatide, weekly high-dose teriparatide, or bisphosphonate on cortical and trabecular bone of vertebra and proximal femur in postmenopausal women with fragility fracture: Sub-analysis by quantitative computed tomography from the TERABIT study.

PURPOSE: The effects of daily teriparatide (D-PTH, 20 µg/day), weekly high-dose teriparatide (W-PTH, 56.5 µg/week), or bisphosphonate (BP) on the vertebra and proximal femur were investigated using quantitative computed tomography (QCT). METHODS: A total of 131 postmenopausal women with a history of fragility fractures were randomized to receive D-PTH, W-PTH, or bisphosphonate (oral alendronate or risedronate). QCT were evaluated at baseline and after 18 months of treatment. RESULTS: A total of 86 participants were evaluated by QCT (Spine: D-PTH: 25, W-PTH: 21, BP: 29. Hip: PTH: 22, W-PTH: 21, BP: 32. Dropout rate: 30.5 %). QCT of the vertebra showed that D-PTH, W-PTH, and BP increased total vBMD (+34.8 %, +18.2 %, +11.1 %), trabecular vBMD (+50.8 %, +20.8 %, +12.2 %), and marginal vBMD (+20.0 %, +14.0 %, +11.5 %). The increase in trabecular vBMD was greater in the D-PTH group than in the W-PTH and BP groups. QCT of the proximal femur showed that D-PTH, W-PTH, and BP increased total vBMD (+2.8 %, +3.6 %, +3.2 %) and trabecular vBMD (+7.7 %, +5.1 %, +3.4 %), while only W-PTH and BP significantly increased cortical vBMD (-0.1 %, +1.5 %, +1.6 %). Although there was no significant increase in cortical vBMD in the D-PTH group, cortical bone volume (BV) increased in all three treatment groups (+2.1 %, +3.6 %, +3.1 %). CONCLUSIONS: D-PTH had a strong effect on trabecular bone of vertebra. Although D-PTH did not increase cortical BMD of proximal femur, it increased cortical BV. W-PTH had a moderate effect on trabecular bone of vertebra, while it increased both cortical BMD and BV of proximal femur. Although BP had a limited effect on trabecular bone of vertebra compared to teriparatide, it increased both cortical BMD and BV of proximal femur.

The Effects of Longer Use of Teriparatide on Clinical and Radiographic Outcomes after Spinal Fusion in Geriatric Patients.

Background: Teriparatide is an anabolic agent for osteoporosis and is believed to improve the bone healing process. Previous studies showed that teriparatide could enhance not only fracture healing but also spine fusion. It has been reported that use of teriparatide could promote the spine fusion process and decrease mechanical complications. However, there was no consensus regarding optimal treatment duration. The purpose of this study was to compare surgical outcomes between short-duration and long-duration teriparatide treatment after lumbar fusion surgery in elderly patients. Materials and Methods: All consecutive patients older than 60 years who underwent 1-level lumbar fusion surgery for degenerative diseases between January 2015 and December 2019 were retrospectively reviewed. Based on the duration of teriparatide treatment (daily subcutaneous injection of 20 µg teriparatide), patients were subdivided into two groups: a short-duration (SD) group (<6 months) and a long-duration (LD) group (≥6 months). Mechanical complications, such as screw loosening, cage subsidence, and adjacent vertebral fractures, were investigated. Postoperative 1-year union rate was also evaluated on computed tomography. Clinical outcomes were recorded using visual analog scale (VAS) and Oswestry Disability Index (ODI). Between-group differences for these radiographic and clinical outcomes were analyzed. Results: Ninety-one patients were reviewed in this study, including sixty patients in the SD group and thirty-one patients in the LD group. Their mean age was 72.3 ± 6.2 years, and 79 patients were female. Mean T-score was -3.3 ± 0.8. Cage subsidence (6.7% vs. 3.2%), screw loosening (28.3% vs. 35.5%), and adjacent vertebral fracture (6.7% vs. 9.7%) were not significantly different between the SD and LD groups. Union rate at 1-year postoperative was 65.0% in the SD group and 87.1% in the LD group (p = 0.028). Both groups showed improvement in VAS and ODI after surgery. However, the differences of VAS from preoperative to 6 months and 1 year postoperative were significantly higher in the LD group. Conclusions: Longer teriparatide treatment after lumbar fusion surgery resulted in a higher union rate at 1-year postoperative than the shorter treatment. Also, it could be more beneficial for clinical outcomes.

Oral daily PTH(1-34) tablets (EB613) in postmenopausal women with low BMD or osteoporosis: a randomized, placebo-controlled, 6-month, phase 2 study.

Anabolic treatment is indicated for high and very-high risk patients with osteoporosis, but acceptance is limited because current anabolic medications require subcutaneous injections. The purpose of this study was to assess the effects of a novel orally administered PTH tablet on serum markers of bone formation (PINP and osteocalcin), bone resorption (crosslinked C-telopeptide [CTX]), BMD, and safety in postmenopausal women with low BMD or osteoporosis. In this 6-mo, double-blind, placebo-controlled study, 161 patients were randomized to oral PTH tablets containing 0.5, 1.0, 1.5, or 2.5 mg or placebo daily. Biochemical markers were assessed at 1, 2, 3, and 6 mo and BMD of LS, TH, and FN was measured at 6 mo. Biochemical marker changes were dose dependent with minimal or no effect at the 2 lowest doses. At the highest dose (2.5 mg once daily), serum PINP and OC levels increased 30% within 1 mo after oral PTH initiation (P < .0001), remained elevated through 3 mo, and were back to baseline at 6 mo. In contrast, serum CTX levels declined 16% and 21% below baseline at 3 and 6 mo, respectively (both P ≤ .02). At 6 mo, 2.5 mg tablets increased mean BMD vs placebo of the LS by 2.7%, TH by 1.8%, and FN by 2.8% (all P ≤ .01). There were no drug-related serious adverse events. The most common adverse events were headache, nausea, and dizziness. In contrast to subcutaneous PTH, the oral PTH tablet appears to increase BMD rapidly by the dual mechanism of stimulating formation and inhibiting bone resorption. This might be the first effective oral anabolic alternative to subcutaneous administration for the treatment of low BMD or osteoporosis.

Despite the superior benefits of bone-building (anabolic) agents and guidelines supporting their use, these medications are used in a minority of patients for whom they are appropriate, in part because they require daily or monthly injections, which limit patient acceptance. An oral anabolic tablet has potential to address this substantial treatment gap. In this double-blind, placebo controlled, dose-finding randomized study, 161 postmenopausal women with low BMD or osteoporosis were treated with varying doses of the active part of PTH(1-34) or placebo given in daily oral tablets for 6 mo. The highest oral PTH tablet dose (2.5 mg) produced an increase in markers of bone formation while simultaneously decreasing the markers of bone breakdown. Significant gains in BMD of the spine and hip were observed at the end of the 6-mo study and there were no significant safety concerns. The 2.5 mg oral PTH tablet dose was well tolerated when patients were instructed to titrate up to the full dose. We conclude that this PTH tablet might be the first effective orally administered bone building medication and should be studied further in treatment of women with osteoporosis.

Cost-effectiveness of romosozumab for the treatment of postmenopausal women with osteoporosis at high risk of fracture in Belgium.

This study evaluated the cost-effectiveness of sequential treatment with romosozumab-to-alendronate compared to alendronate monotherapy and teriparatide-to-alendronate, in postmenopausal osteoporotic women from a Belgian healthcare perspective. Romosozumab-to-alendronate was found to be cost-effective compared to alendronate monotherapy and dominant compared to teriparatide-to-alendronate for osteoporotic women at high risk of fracture in Belgium. PURPOSE: This study aimed to evaluate the cost-effectiveness of sequential treatment with romosozumab followed by alendronate compared to alendronate monotherapy and teriparatide followed by alendronate, in postmenopausal osteoporotic women at high risk of fracture, from a Belgian healthcare perspective. Romosozumab is reimbursed in Belgium since December 2021. METHODS: A Markov microsimulation model was used to evaluate the cost-effectiveness of romosozumab-to-alendronate compared to alendronate monotherapy and to teriparatide-to-alendronate over a lifetime horizon. Patients transition between five different health states every 6 months based on fracture risks or death. The model was populated with Belgium-specific epidemiological and cost data, where available. The fracture risk reduction of romosozumab treatment was collated from the ARCH study, and from a published network meta-analysis. Costs were included from a healthcare perspective (NIHDI). Cost-effectiveness was reported in terms of costs per quality-adjusted life year (QALY), reported in Euro (€) 2022. Deterministic (DSA) and probabilistic sensitivity analyses (PSA) were performed. RESULTS: Romosozumab-to-alendronate was associated with 0.12 additional QALYs at an additional cost of €2314 compared to alendronate monotherapy, resulting in an ICER of €19,978. Compared to teriparatide-to-alendronate, romosozumab-to-alendronate was found to be dominant, with higher QALYs and lower costs. The base-case results were robust to uncertainty in the input parameters when conducting the sensitivity analysis. CONCLUSION: Sequential treatment with romosozumab followed by alendronate was found to be cost-effective compared to alendronate monotherapy and dominant compared to teriparatide followed by alendronate for postmenopausal women with osteoporosis at high risk of fracture in Belgium.

Differential effects of teriparatide, denosumab and zoledronate on hip structural and mechanical parameters in osteoporosis; a real-life study.

PURPOSE: The aim of this study was to evaluate changes in hip geometry parameters following treatment with teriparatide (TPD), denosumab (Dmab) and zoledronate (ZOL) in real-life setting. METHODS: We studied 249 patients with osteoporosis (OP) with mean [SD] age of 71.5 [11.1] years divided into 3 treatment groups; Group A received TPD; n = 55, Group B (Dmab); n = 116 and Group C (ZOL); n = 78 attending a routine metabolic bone clinic. Bone mineral density (BMD) was measured by DXA at the lumbar spine (LS), total hip (TH) and femoral neck (FN) prior to treatment and after 2 years (Group A), after a mean treatment duration of 3.3 [1.3] years (Group B) and after 1, 2 and 3 doses of ZOL (Group C) to assess treatment response. Hip structural analysis (HSA) was carried out retrospectively from DXA-acquired femur images at the narrow neck (NN), the intertrochanter (IT) and femoral shaft (FS). RESULTS: Changes in parameters of hip geometry and mechanical strength were seen in the following treatment. Percentage change in cross-sectional area (CSA): 3.56[1.6] % p = 0.01 and cross-sectional moment of inertia (CSMI): 4.1[1.8] % p = 0.029 increased at the NN only in Group A. Improvement in HSA parameters at the IT were seen in group B: CSA: 3.3[0.67]% p < 0.001, cortical thickness (Co Th): 2.8[0.78]% p = 0.001, CSMI: 5.9[1.3]% p < 0.001, section modulus (Z):6.2[1.1]% p < 0.001 and buckling ratio (BR): - 3.0[0.86]% p = 0.001 with small changes at the FS: CSA: 1.2[0.4]% p = 0.005, Z:1.6 [0.76]%, p = 0.04. Changes at the IT were also seen in Group C (after 2 doses): CSA: 2.5[0.77]% p = 0.017, Co Th: 2.4[0.84]% p = 0.012, CSMI: 3.9[1.3]% p = 0.017, Z:5.2[1.16]% p < 0.001 and BR: - 3.1[0.88]% p = 0.001 and at the NN (following 3 doses): outer diameter (OD): 4.0[1.4]% p = 0.0005, endocortical diameter(ED): 4.3[1.67% p = 0.009, CSA:5.2[1.8]% p = 0.003, CSMI: 9.3[3.8]% p = 0.019. CONCLUSIONS: Analysis of the effect of OP therapies on hip geometry is useful in understanding the mechanisms of their anti-fracture effect and may provide additional information on their efficacy.

Effects of four-year cyclic versus two-year daily teriparatide treatment on volumetric bone density and bone strength in postmenopausal women with osteoporosis.

PURPOSE: To evaluate the effects of cyclic vs daily teriparatide treatment (TPTD) on volumetric bone mineral density (vBMD) and bone strength at the hip and spine in women who were previously untreated. METHODS: A total of 86 women were randomized to a 24-month open label treatment of either daily TPTD (20 µg daily) or cyclic TPTD (20 µg daily for 3 months followed by 3 months off). During a 2-year extension, women in the daily TPTD group were switched to alendronate (ALN) and those in the cyclic TPTD group continued on cyclic TPTD (without any ALN). QCT images were acquired at baseline, 2-years (n = 54) and 4-years (n = 35) and analyzed for volumetric integral, cortical and trabecular bone mineral density (vBMD) and bone strength (by finite element analysis) at the hip and spine. The primary analysis presented here compared the responses across equal total TPTD doses (2 years daily vs 4 years cyclic). RESULTS: In the spine, integral vBMD and strength increased substantially after 2 years daily and 4 years cyclic TPTD, with no significant differences (vBMD +12 % vs +11 %, respectively, p = 0.70; spine strength +21 % vs +16 %, respectively, p = 0.35). At the hip, the gains were smaller, but again no significant differences were detected between the groups for the increases in either vBMD (+2 % in both groups, p = 0.97) or hip strength (3 % vs 3 %, p = 0.91). In the spine, the vBMD increment was about twice as large in the trabecular vs peripheral compartment; in the hip, significant vBMD gain was seen only in the trabecular compartment. CONCLUSIONS: The gains in volumetric BMD and bone strength for an equivalent dose of TPTD did not depend on whether it was administered every day over two years or cyclically over four years.

Efectos de la administración local de PTH 1-34 a bajas dosis en un modelo experimental de periodontitis: estudio piloto / Local effects of low dose of PTH 1-34 on experimental periodontitis: pilot study

La periodontitis es una patología inflamatoria que aumenta la resorción de hueso alveolar (HA), pérdida de la inserción dentaria y posible exfoliación. Evaluamos el efecto de la administración intermitente de bajas dosis de parathormona (PTH) 1-34 sobre la recuperación de la masa ósea pérdida en un modelo experimental de periodontitis inducida por una ligadura periodontal (LP) con hilo de algodón alrededor de la pieza dentaria. Las ratas fueron divididas luego de 5 días en instaurada la periodontitis en: CT LP sin trata-miento y PTH LP tratados con 0,2 µg/kg PTH 1-34 subcutánea local, tres veces por semana por 17 días. El control absoluto fue un tercer grupo sin LP (CT). Se estudiaron parámetros antropométricos, bioquímicos e histomosfométricos en tibias y hemimandibulas. La calcemia, fosfatemia, CTX sérico, PTHi y vo-lumen óseo (BV/TV%) de tibias fueron similares en los tres grupos. El BV/TV% del HA fue significativamente menor en PTH LP respecto de CT pero mayor que CT LP (p<0.05). La pérdida ósea de HA porcentual fue significativamente mayor en CT LP (p<0.05). La altura del ligamento periodontal fue significativamente menor en PTH LP que en CT (p<0.05) y mayor respecto de CT LP, sin alcanzar diferencias significativas. Los resultados del presente estudio piloto sugieren que la administración intermitente de PTH en bajas dosis y durante un periodo de tiempo corto disminuye la progresión de la enfermedad periodontal sin generar efectos sistémicos. Como no se logró regenerar totalmente el tejido periodontal se requieren estudios adicionales. (AU)

Periodontitis is an inflammatory chronic disease with high prevalence in adults that induces a progressive alveolar bone (AB) loss leading to tooth loss. Experimental periodontitis can be induced in rats by cotton ligature placement (LP) in the gingival sulcus around the molar teeth. The biofilm accumulation and disruption of the gingival epithelium lead to bone resorption. We investigated whether intermittent administration of a low dose of PTH 1-34 may recover the alveolar bone loss in the experimental periodontitis induced in female Wistar rats. Animals were randomly divided in two groups which were subcutaneously injected with: saline solution (CT LP) or 0,2 µg/kg PTH 1-34 (PTH LP) three times per week during 17 days. Unligated rats were taken as healthy controls (CT). Anthropometric, biochemical and histologic analysis of tibia and hemimandible were done. No differences in serum calcium, phosphorus, CTX, PTHi or subchondral tibia bone volume (BV/TV%) were observed between the three groups. AB BV/TV% was significantly lower in PTH LP than in CT but higher than in CT LP (p<0.05). The highest percentage of AB loss was observed in CT LP. The height of periodontal ligament was lower in PTH LP than in CT (p<0.05) but not significantly higher than CT LP.The increase in AB loss by experimental periodontitis appears to be corrected by the intermittent administration of low doses of PTH without systemic effect. As the recovery of periodontal tissue was only partial, additional studies should be done.

The Effect of Daily Teriparatide versus One-Time Annually Zoledronic Acid Administration After Transforaminal Lumbar Interbody Fusion in Osteoporotic Patients.

PURPOSE: The research aimed to compare the therapeutic effect of teriparatide (TPTD) and zoledronic acid (ZOL) therapy on bone formation and spinal fusion in patients with osteoporosis (OP) who underwent transforaminal lumbar interbody fusion (TLIF). METHODS: On the basis of different anti-OP treatment options, the TPTD group was treated daily with TPTD (20 µg. ih. qd) for at least 6 months, while the ZOL group was treated with a single dose of ZOL (5 mg. ivgtt. st) postoperatively. The visual analogue scale (VAS), Oswestry Disability Index (ODI), bone mineral density (BMD), and concentration of bone turnover markers before, 6, and 12 months after surgery were evaluated. X-ray and three-dimensional computed tomography scans were performed at 6 and 12 months postoperatively to assess interbody fusion. RESULTS: The number of patients in the TPTD and ZOL groups was 29 and 38 patients, respectively. The VAS and ODI scores in both groups were significantly reduced at 6 and 12 months after TLIF. Compared with that of baseline, the lumbar spine BMD of TPTD patients increased significantly from 0.716±0.137 g/cm2 to 0.745±0.124 g/cm2 and 0.795±0.123 g/cm2 at 6 and 12 months, respectively, and was significantly higher than that of the ZOL group at 12 months (0.720±0.128 g/cm2). The bone formation marker, P1NP, in the TPTD group increased significantly (145.48±66.64 ng/mL and 119.55±88.27 ng/mL) compared with baseline (44.67±25.15 ng/mL) and in the ZOL group (28.82±19.76 ng/mL and 29.94±20.67 ng/mL) at 6 and 12 months, respectively. The fusion rates in the TPTD and ZOL groups were 57% and 45% at 6 months, without statistical significance. However, TPTD had a more statistically significant positive influence on fusion rate than ZOL at 12 months (86% vs 70%). CONCLUSION: TPTD was more efficient than ZOL in bone formation and spinal fusion in OP patients who underwent TLIF.

Romosozumab versus Teriparatide for the Treatment of Postmenopausal Osteoporosis: A Systematic Review and Meta-analysis through a Grade Analysis of Evidence.

OBJECTIVE: To provide a systematic review about the efficacy and safety of romosozumab and teriparatide for the treatment of postmenopausal osteoporosis. METHOD: Randomized controlled trials (RCTs) were searched from electronic databases, including PubMed (1996 to June 2019), Embase (1980 to June 2019), Cochrane Library (CENTRAL, June 2019), Web of Science (1998 to June 2019), and others. The primary outcomes included the following: the percentage change in bone mineral density of lumbar spine and total hip from baseline at month 6 and month 12 in each group. The secondary outcomes included the following: the percentage change in bone mineral density of femoral neck from baseline at month 6 and month 12 in each group and the incidence of adverse events at month 12 in each group. RESULTS: Four studies containing 1304 patients met our selection criteria. The result of our analysis indicated that romosozumab showed better effects in improving BMD of lumbar spine (month 6: MD = 3.54, 95% CI [3.13, 3.94], P<0.001; month 12: MD = 4.93, 95% CI [4.21, 5.64], P<0.001), total hip (month 6: MD = 2.27, 95% CI [0.62, 3.91], P = 0.007; month 12: MD = 3.17, 95% CI [2.68, 3.65], P<0.001), and femoral neck (month 6: MD = 2.30, 95% CI [0.51, 4.08], P = 0.01; month 12: MD = 3.04, 95% CI [2.29, 3.78], P<0.001). Also, the injection-site reaction was less (month 12: RR = 2.84, 95% CI [1.22, 6.59], P = 0.02), but there were no significant difference in the incidence of serious adverse events (month 12: RR = 0.78, 95% CI [0.46, 1.33], P = 0.37) and death (month 12: RR = 0.61, 95% CI [0.08, 4.62], P = 0.63). CONCLUSION: Based on the available studies, our current results demonstrate that romosozumab was better than teriparatide both in terms of efficacy and side effects.

Extracorporeal Shock Wave Combined with Teriparatide-Loaded Hydrogel Injection Promotes Segmental Bone Defects Healing in Osteoporosis.

BACKGROUND: Osteoporosis is a systemic bone disease characterized by decreased bone density and deterioration of bone microstructure, leading to an increased probability of fragility fractures. Once segmental bone defect occurs, it is easy to cause delayed union and nonunion. METHODS: The aim of this study is to investigate the efficacy of extracorporeal shock wave (ESW) and teriparatide-loaded hydrogel (T-Gel) combined strategy on the cell activity and differentiation of osteoporosis derived bone marrow mesenchymal stem cells (OP-BMSCs) in vitro and bone regeneration in osteoporotic segmental bone defects in vivo. RESULTS: In vitro, the strategy of combining ESW and T-Gel significantly enhanced OP-BMSCs proliferation, survival, migration, and osteogenic differentiation by up-regulating the alkaline phosphatase activity, mineralization, and expression of runt-related transcription factor-2, type I collagen, osteocalcin, and osteopontin. In the segmental bone defect models of osteoporotic rabbits, Micro-CT evaluation and histological observation demonstrated this ESW-combined with T-Gel injection significantly induced bone healing by enhancing the osteogenic activity of the local microenvironment in osteoporotic defects. CONCLUSION: In conclusion, ESW-combined with T-Gel injection could regulate the poor osteogenic microenvironment in osteoporotic defects and show potential for enhancing fragility fractures healing.

Osteoporosis - risk factors, pharmaceutical and non-pharmaceutical treatment.

Osteoporosis is a metabolic disease of the skeletal system which currently affects over 200 million patients worldwide. The WHO criteria define osteoporosis as low bone mineral density, with a T-score ≤ -2.5 found in the spine, the neck of the femur, or during a full hip examination. Osteoporosis considerably reduces a patient's quality of life. QoL should be carefully evaluated before fractures occur to enable the development of an appropriate treatment plan. The progression of osteoporosis may be significantly inhibited by following a proper diet, leading a healthy lifestyle, taking dietary supplements, and receiving appropriate treatment. Education and the prevention of the disease play a major role. Potentially modifiable risk factors for osteoporosis are vitamin D deficiency, smoking, alcohol consumption, low calcium intake, low or excessive phosphorus intake, protein deficiency or a high-protein diet, excessive consumption of coffee, a sedentary lifestyle or lack of mobility, and insufficient exposure to the sun. Pharmaceutical treatment for osteoporosis involves bisphosphonates, calcium and vitamin D3, denosumab, teriparatide, raloxifene, and strontium ranelate. Data indicates that 30%-50% of patients do not take their medication correctly. Other methods of treatment include exercise, kinesitherapy, treatment at a health resort, physical therapy, and diet.

Oral Delivery of Parathyroid Hormone Using a Triple-Padlock Nanocarrier for Osteoporosis via an Enterohepatic Circulation Pathway.

Intermittent subcutaneous (S.C.) injection of teriparatide [PTH (1-34)] is one of the effective therapies to cure osteoporosis. However, a long-term repeated administration of teriparatide by S.C. to the patients is highly challenging. Herein, a triple padlock nanocarrier prepared by a taurocholic acid-conjugated chondroitin sulfate A (TCSA) is designed to develop an oral dosage form of recombinant human teriparatide (rhPTH). Oral administration of TCSA/rhPTH to the bilateral ovariectomized (OVX) rats resulted in the recovery of the bone marrow density and healthy serum bone parameters from the severe osteoporotic conditions. Also, it enhanced new bone formation in the osteoporotic tibias. This triple padlock oral delivery platform overcame the current barriers associated with teriparatide administration and exhibited a promising therapeutic effect against osteoporosis.

Teriparatide and exercise improve bone, skeletal muscle, and fat parameters in ovariectomized and tail-suspended rats.

INTRODUCTION: Although teriparatide (TPTD) and exercise may improve osteoporosis, muscle atrophy, and fat metabolism during ageing, the effects of treatment with a combination of TPTD and exercise on these factors remain unclear. Therefore, this study examined the effects of TPTD and exercise on bone, skeletal muscle, and fat in ovariectomized and tail-suspended rats. MATERIALS AND METHODS: Seven-month-old female Wistar rats were ovariectomized and subjected to tail suspension. The rats were then randomized into one of the following four groups (n = 20/group) after 4 weeks: control group, treated with TPTD vehicle and no exercise; TPTD group (30 µg/kg TPTD, 3 days/week); Exercise group (treadmill at 12 m/min, 60 min/day, 5 days/week); and Combined group treated with TPTD and treadmill exercise. After 1 and 8 weeks of treatment, bone, skeletal muscle, and fat tissue parameters were evaluated. RESULTS: TPTD improved bone mineral density (BMD), bone structure, bone strength at the femoral metaphysis, and the percentage of skeletal muscle mass, and decreased the percentage of fat mass and the adipose volume in the bone marrow. Treadmill exercise increased BMD, bone strength of cancellous bone, and the percentage of skeletal muscle mass, and decreased the percentage of fat mass as seen on dual-energy X-ray absorptiometry. Furthermore, combined treatment significantly affected BMD, bone structure, and bone strength of cortical bone at the femoral diaphysis. CONCLUSION: TPTD or treadmill exercise improved bone, skeletal muscle, and fat mass. Combination therapy with TPTD and exercise had synergistic effects on BMD, structure, and bone strength in ovariectomized, tail-suspended rats.

Healing of erosions in rheumatoid arthritis remains elusive: results with 24 months of the anabolic agent teriparatide.

Objective: Erosion healing in rheumatoid arthritis (RA) is difficult to demonstrate. This extension study aimed to determine whether 2 years of teriparatide (TPTD) produces erosion healing. Method: Subjects in a previous 12 month randomized controlled trial of TPTD in RA were invited to receive 12 additional months of open-label TPTD. Eleven of the 24 original subjects were enrolled in the extension study, six of whom received TPTD in the final 12 months only. Subjects receiving 24 months of TPTD were assessed for reduction in erosion volume from baseline using computed tomography. We also compared erosion volumes between 12 and 24 months of TPTD. Large erosions in subjects receiving TPTD for 24 months were examined for volume change. Results: In the six patients who received 24 months of TPTD, there was no significant change in erosion volume at the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints compared with baseline. The six subjects who received 24 months of TPTD had similar changes in erosion volume to the five who received 12 months of TPTD, in MCP (p = 0.17) and PIP (p = 0.63) joints. Assessment of large erosions in those receiving TPTD for 24 months showed no evidence of erosion healing. Conclusion: While this extension study was too small to be conclusive, we observed no evidence of reduction in erosion volume with the addition of TPTD for 24 months in subjects with RA in whom disease activity was controlled on a tumour necrosis factor inhibitor. This is consistent with our negative findings at 12 months.

Effects of follow-on therapy after denosumab discontinuation in patients with postmenopausal osteoporosis.

OBJECTIVES: To clarify the effects of follow-on therapy after denosumab (DMAb) discontinuation. METHODS: In this retrospective, multicenter study, postmenopausal patients with osteoporosis who were previously treated by oral bisphosphonates (BP) (n = 26) or teriparatide (TPTD) (n = 27) were switched to DMAb (administered 2.6 times), and then discontinued. Patients (73.1 years, T-scores of the lumbar spine [LS] - 2.7 and femoral neck [FN] - 2.2) were switched to either (1) raloxifene (RAL) (n = 13) or BP [(2) weekly or monthly BP (wmBP) (n = 29) or (3) zoledronate (ZOL) (n = 11)], based on each physician's decision (mean interval after final DMAb administration was 7.2 months). Bone mineral density (BMD) at final DMAb administration were set as baseline. RESULTS: Changes in LS BMD at 1.5 years after final DMAb administration were -2.7% in the RAL, 0.7% in the wmBP, and 1.9% in the ZOL (p = .31 between groups), and in FN BMD were -3.8%, -0.8%, and 1.8%, respectively (p = .02 between the RAL and ZOL; p = .048 between the RAL and BP). Clinical vertebral fracture incidence during 1.5 years after final DMAb administration was 23.1% in the RAL, 3.4% in the wmBP, and 0.0% in the ZOL (p = .048 between the RAL and ZOL; p = .015 between the RAL and BP). No significant differences were observed in these parameters between the wmBP and ZOL. CONCLUSION: These results may contribute to the selection of adequate follow-on therapy after DMAb discontinuation, although further investigations are required.

Assessment of the efficacy of teriparatide treatment for osteoporosis on lumbar fusion surgery outcomes: a systematic review and meta-analysis.

Treatment of osteoporosis with medications like teriparatide, a parathyroid hormone, is known to improve bone density and reduce the risk of osteoporotic vertebral fractures. Anecdotal and limited surgical series have described the utility of this treatment for osteoporotic patients prior to spinal fusion surgery, but there is variability in adoption of this strategy as well as consensus regarding optimal treatment duration before and after surgery. In this study, the clinical results of the use of teriparatide for this application are reviewed and critically examined. We conducted a systematic review of electronic databases using different MeSH terms from 1980 to 2020. Pooled and subgroup analyses were performed using fixed and random effect models based upon the heterogeneity (I2). The results were reported as either mean difference (MD) or odds ratio (OR) with 95% confidence interval (CI). A total of 771 patients from 12 studies were identified. Three hundred seventy-seven patients (90.8% females) were treated with teriparatide. Lumbar spinal fusion rates were significantly higher among patients who received teriparatide compared to the non-teriparatide group (OR 2.15, 95%CI 1.56-2.97, p < 0.00001). Subgroup analysis revealed that patients receiving teriparatide demonstrated 2.12-fold and 2.23-fold higher likelihood of fusion compared to those in the bisphosphonate (OR 2.12, 95%CI 1.45-3.11, p = 0.0001) and placebo (OR 2.23, 95%CI 1.22-4.08, p = 0.009) cohorts, respectively. The treatment effect of teriparatide was associated with significantly reduced subsequent vertebral fractures (OR 0.16, 95%CI 0.06-0.41, p = 0.0002), sagittal malalignment (MD - 3.85, 95%CI: -6.49 to - 1.21, p = 0.004), limb visual analogue score (VAS) (MD - 0.36, 95%CI - 0.64 to - 0.09, p = 0.008), and spinal VAS (MD - 0.24, 95%CI - 0.44 to - 0.04, p = 0.02) compared to the non-teriparatide group. Patients using teriparatide had 30% less likelihood of screw loosening at last follow-up compared to the non-teriparatide group; however, this was not statistically significant (OR 0.70, 95%CI 0.43-1.14, p = 0.15). There did not exist any statistically significant difference between the two comparative groups in terms of pseudoarthrosis (OR 0.54, 95%CI 0.24-1.21, p = 0.13), cage subsidence (OR 1.30, 95%CI 0.38-4.52, p = 0.68), and bone mineral density (MD 0.04, 95%CI - 0.19-0.29, p = 0.74) at last follow-up examination. This meta-analysis corroborates the effectiveness of teriparatide resulting in higher fusion rates. Further study is required to determine the optimal duration of treatment and timing of surgery.

Prevention of bone loss and improvement of pain-related behavior in hind limb-unloaded mice by administration of teriparatide and bisphosphonate.

OBJECTIVES: There are few reports on the comparison between teriparatide (PTH) and bisphosphonate (BP) in terms of osteoporosis pain-related behavior and immunohistochemical findings. The aims of this study were to evaluate skeletal pain associated with osteoporosis and to examine the inhibitory effect of PTH and BP on pain and bone loss in hind limb-unloaded (HU) mice. The mechanism of osteoporotic pain in HU mice was evaluated by examining pain-related behavior and immunohistochemical findings. The effects of PTH and alendronate (ALN), a potent osteoclast inhibitor, on these parameters were also assessed. METHODS: Eight-week-old male ddY mice were tail-suspended for 2 weeks and assigned to four groups: hind limb-loaded (HL) mice with only tail suspension treated with vehicle; HU mice with tail suspension treated with vehicle; HU mice treated with PTH; and HU mice treated with ALN. Starting immediately after reloading, vehicle, PTH, or ALN was injected subcutaneously. After a 2-week treatment, mechanical sensitivity was examined using von Frey filaments. Bilateral hind limbs were removed for micro-computed tomography, immunohistochemical analysis, and messenger RNA (mRNA) expression analysis. RESULTS: HU mice with tail suspension developed bone loss and mechanical hyperalgesia in the hind limbs. The HU mice showed an increased osteoclasts and sclerostin-positive cells in the hind limb bone. Furthermore, PTH and ALN both prevented HU-induced bone loss and mechanical hyperalgesia in the osteoporotic animal models. Histological examination of the hind limb bone revealed that, similar to ALN, PTH inhibited the osteoclasts and sclerostin-positive cells. The mRNA levels of TNFα and IL-6 tended to decrease with ALN or PTH treatment compared with those without any treatment. CONCLUSIONS: Treatment with PTH as well as BP prevented bone loss, mechanical hyperalgesia, osteoclast increase, and osteocyte increase. Similar to BP, the inhibitory effect of PTH on osteoclasts might contribute to the improvement of skeletal pain.

Atypical femoral fracture associated with delayed union for which the cessation of alendronate and daily administration of teriparatide contributed to fracture healing: histopathological evidence of the enhancement in bone formation parameters.

A female patient with systemic lupus erythematosus developed an atypical femoral fracture of the left femur after 5 years of glucocorticoid and alendronate therapy. We performed intramedullary nailing. However, 1 week later, we performed a revision surgery using a locking plate and an iliac bone graft because of displacement at the fracture site. At this stage, alendronate was discontinued and daily teriparatide was introduced and continued for 24 months. Twenty months after the revision surgery, a re-revision surgery was performed with an iliac bone graft because of breakage of the locking plate and fracture non-union. Fracture healing was eventually obtained 15 months after the re-revision surgery. Biopsies of the ilium before the treatment and 20 months after daily teriparatide treatment were evaluated. The histology revealed that proliferating osteoid and cuboidal osteoblasts were detected around the osteoid tissue after teriparatide treatment. Bone histomorphometry findings showed that bone volume parameters and osteoid parameters prominently increased with the teriparatide treatment, but not bone resorption parameters. Laboratory findings revealed the elevation of bone-specific alkaline phosphatase (24 U/L at 7 months) compared to its pre-teriparatide level (8.1 U/L) and increased bone mineral density of the hip (from -0.2 to 0.0 in T-score). These data indicated that the discontinuation of alendronate and initiation of teriparatide treatment activated bone-forming ability in our patient and may have contributed to fracture healing.