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.

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.

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.

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.

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.

Use of teriparatide prior to lumbar fusion surgery lowers two-year complications for patients with poor bone health.

INTRODUCTION: Poor bone health can create challenges in management which are amplified for patients undergoing spinal fusion. Although previously shown to improve outcomes postoperatively, the impact of preoperative teriparatide use on long-term complications remains unclear. In this study, we investigated the complication rates within two years of surgery for osteoporotic and osteopenic patients using teriparatide prior to lumbar fusion procedures. METHODS: Patients with poor bone health undergoing any lumbar fusion surgery at a single institution between 2008 and 2018 were identified and subsequently divided into two groups as teriparatide and non-teriparatide group. Baseline demographics, patient and surgery related factors, and two-year complications were collected through a retrospective chart review. Multivariable logistic regression was performed to evaluate the association between teriparatide usage and development of any related postoperative complication. RESULTS: A total of 42 and 114 patients were identified for the teriparatide and non-teriparatide groups, respectively. The median age (IQR) for the teriparatide group was 62 years (55.8-68.8), while the non-teriparatide group had a median (IQR) age of 70 years (64-75.8). Overall, there were no statistically significant differences in terms of individual complications between the groups. However, on adjusted regression analysis, teriparatide use was associated with significantly lower odds of related complications for lumbar fusion patients (p = 0.049). CONCLUSION: Teriparatide use prior to lumbar fusion procedures resulted in reduced rate of osteoporosis-related complications within two years postoperatively. Results suggest improved outcomes might be seen in patients with osteopenia and osteoporosis when pre-treating with teriparatide.

Romosozumab: A Review in Postmenopausal Osteoporosis.

Romosozumab (Evenity®), a humanized monoclonal antibody, promotes bone formation and inhibits bone resorption by inhibiting sclerostin, a protein involved in the regulation of bone formation. Subcutaneous romosozumab is approved in several countries, including those of the EU for treating severe osteoporosis as well as in the USA for osteoporosis in postmenopausal women at high risk of fracture. In pivotal phase III trials (FRAME and ARCH), 12 months' once-monthly romosozumab 210 mg significantly reduced vertebral and clinical fracture risk versus placebo and oral alendronate in postmenopausal women with osteoporosis. After patients transitioned from romosozumab to 12-24 months of subcutaneous denosumab or oral alendronate, fracture risks were significantly improved versus placebo-to-denosumab and alendronate-only treatment. In these trials and a phase IIIb trial, romosozumab significantly increased bone mineral density (BMD) relative to placebo, alendronate and subcutaneous teriparatide at 12 months, with these benefits maintained 12-24 months after patients transitioned from romosozumab to alendronate or denosumab in pivotal trials. Romosozumab had a generally manageable tolerability profile. While further clinical experience is needed to more definitively establish its efficacy and safety, including its CV safety, romosozumab extends the treatment options in postmenopausal women with osteoporosis who have a high risk of fracture and in those who have failed or are intolerant to other available osteoporosis therapy.

Osteocytic Osteolysis in PTH-treated Wild-type and Rankl-/- Mice Examined by Transmission Electron Microscopy, Atomic Force Microscopy, and Isotope Microscopy.

To demonstrate the ultrastructure of osteocytic osteolysis and clarify whether osteocytic osteolysis occurs independently of osteoclastic activities, we examined osteocytes and their lacunae in the femora and tibiae of 11-week-old male wild-type and Rankl-/- mice after injection of human parathyroid hormone (PTH) [1-34] (80 µg/kg/dose). Serum calcium concentration rose temporarily 1 hr after PTH administration in wild-type and Rankl-/- mice, when renal arteries and veins were ligated. After 6 hr, enlargement of osteocytic lacunae was evident in the cortical bones of wild-type and Rankl-/- mice, but not so in their metaphyses. Von Kossa staining and transmission electron microscopy showed broadly demineralized bone matrix peripheral to enlarged osteocytic lacunae, which contained fragmented collagen fibrils and islets of mineralized matrices. Nano-indentation by atomic force microscopy revealed the reduced elastic modulus of the PTH-treated osteocytic perilacunar matrix, despite the microscopic verification of mineralized matrix in that region. In addition, 44Ca deposition was detected by isotope microscopy and calcein labeling in the eroded osteocytic lacunae of wild-type and Rankl-/- mice. Taken together, our findings suggest that osteocytes can erode the bone matrix around them and deposit minerals on their lacunar walls independently of osteoclastic activity, at least in the murine cortical bone. (J Histochem Cytochem 68: -XXX, 2020).

Effect of Teriparatide on Bone Remodeling and Density in Premenopausal Idiopathic Osteoporosis: A Phase II Trial.

CONTEXT: Premenopausal women with idiopathic osteoporosis (IOP) have abnormal skeletal microarchitecture and variable tissue-level bone formation rate (BFR). OBJECTIVES: Compare 6 months (M) of teriparatide versus placebo on areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA), bone turnover markers (BTMs) and BFR at 3M by quadruple-labeled transiliac biopsy. Characterize 12M and 24M effects of teriparatide on aBMD and whether BTMs and BFR predict response. DESIGN: 6M phase 2 randomized controlled trial (RCT) followed by open extension. SETTING: Tertiary referral centers. PATIENTS: Premenopausal women with IOP. INTERVENTIONS: A total of 41 women were randomized to either teriparatide 20 mcg (n = 28) or placebo (n = 13). After 6M, those on placebo switched to teriparatide for 24M; those on teriparatide continued for 18M. MAIN OUTCOME MEASURES: 6M RCT: Between-group differences in lumbar spine (LS) aBMD (percent change from baseline), 3M BFR, and hypercalcemia. Open-label extension: Within-group change in LS aBMD over 12M and 24M. Secondary outcomes included aBMD change at other sites and relationship between BTMs, BFR, and changes in aBMD. FINDINGS: Over 6M, LS aBMD increased by 5.5% (95% CI: 3.83, 7.19) in teriparatide and 1.5% (95% CI: -0.73, 3.83) in placebo (P = 0.007). There were increases in 3M BTMs, and BFR (cancellous and endocortical BFR: between-groups P = 0.004). Over 24M, teriparatide increased LS aBMD by 13.2% (95% CI: 10.3, 16.2), total hip by 5.2% (95% CI: 3.7, 6.7) and femoral neck by 5.0% (95% CI: 3.2, 6.7; all P ≤ 0.001). Serum N-terminal propeptides of procollagen type 1 (P1NP) and 3M endocortical BFR were moderately associated with LS aBMD response. Teriparatide was well-tolerated. CONCLUSIONS: Teriparatide increased BFR and formation markers and was associated with marked aBMD improvements in most premenopausal women (82%) with IOP.

Regional improvements in lumbosacropelvic Hounsfield units following teriparatide treatment.

OBJECTIVE: Opportunistic Hounsfield unit (HU) determination from CT imaging has been increasingly used to estimate bone mineral density (BMD) in conjunction with assessments from dual energy x-ray absorptiometry (DXA). The authors sought to compare the effect of teriparatide on HUs across different regions in the pelvis, sacrum, and lumbar spine, as a surrogate measure for the effects of teriparatide on lumbosacropelvic instrumentation. METHODS: A single-institution retrospective review of patients who had been treated with at least 6 months of teriparatide was performed. All patients had at least baseline DXA as well as pre- and post-teriparatide CT imaging. HUs were measured in the pedicle, lamina, and vertebral body of the lumbar spine, in the sciatic notch, and at the S1 and S2 levels at three different points (ilium, sacral body, and sacral ala). RESULTS: Forty patients with an average age of 67 years underwent a mean of 20 months of teriparatide therapy. Mean HUs of the lumbar lamina, pedicles, and vertebral body were significantly different from each other before teriparatide treatment: 343 ± 114, 219 ± 89.2, and 111 ± 48.1, respectively (p < 0.001). Mean HUs at the S1 level for the ilium, sacral ala, and sacral body were also significantly different from each other: 124 ± 90.1, -10.7 ± 61.9, and 99.1 ± 72.1, respectively (p < 0.001). The mean HUs at the S2 level for the ilium and sacral body were not significantly different from each other, although the mean HU at the sacral ala (-11.9 ± 52.6) was significantly lower than those at the ilium and sacral body (p = 0.003 and 0.006, respectively). HU improvement occurred in most regions following teriparatide treatment. In the lumbar spine, the mean lamina HU increased from 343 to 400 (p < 0.001), the mean pedicle HU increased from 219 to 242 (p = 0.04), and the mean vertebral body HU increased from 111 to 134 (p < 0.001). There were also significant increases in the S1 sacral body (99.1 to 130, p < 0.05), S1 ilium (124 vs 165, p = 0.01), S1 sacral ala (-10.7 vs 3.68, p = 0.04), and S2 sacral body (168 vs 189, p < 0.05). CONCLUSIONS: There was significant regional variation in lumbar and sacropelvic HUs, with most regions significantly increasing following teriparatide treatment. The sacropelvic area had lower HU values than the lumbar spine, more regional variation, and a higher degree of correlation with BMD as measured on DXA. While teriparatide treatment resulted in HUs > 110 in the majority of the lumbosacral spine, the HUs in the sacral ala remained suggestive of severe osteoporosis, which may limit the effectiveness of fixation in this region.

Extremely elevated serum alkaline phosphatase level upon treatment with teriparatide: a case report.

BACKGROUND: Teriparatide is a homolog of human parathyroid hormone (1-34), which is approved for the treatment of postmenopausal and glucocorticoid-induced osteoporosis. Several minor and transient side effects have been reported for teriparatide. However, controversial findings showed an increased risk of more significant adverse effects, including osteosarcoma in humans, although this finding has been demonstrated primarily in murine models. CASE PRESENTATION: We present a case of a 22-year-old Persian man with a previous history of systemic lupus erythematosus and glucocorticoid-induced osteoporosis. He had a previous history of joint hypermobility, idiopathic kyphoscoliosis, mitral valve prolapse, and bilateral congenital inguinal hernia, which were probably compatible with an inherited connective tissue disease. He was treated with teriparatide for 7 months because of glucocorticoid-induced osteoporosis. He was referred with a complaint of generalized bone pain and an extremely elevated serum alkaline phosphatase concentration of 6480 U/L (normal range, 80-306). A whole-body bone scan revealed a diffuse increased osseous uptake. Furthermore, the patient's systemic lupus erythematosus was clinically inactive on the basis of laboratory findings during this period. The medication was discontinued, and the patient's serum alkaline phosphatase level began to decline. CONCLUSIONS: To the best of our knowledge, this is the first case of an osteoblast hyperactivation state observed during treatment with teriparatide. It appears that the osteoblastogenic effect of teriparatide might induce this condition and, most likely, osteosarcoma in certain populations. However, the potential influence of the patient's young age, systemic lupus erythematosus, underlying inherited connective tissue disease, and medication use cannot be ignored. The potential risk factors of this side effect shall be studied in specific subpopulations of patients with osteoporosis in future studies.

Cardiovascular Safety of Abaloparatide in Postmenopausal Women With Osteoporosis: Analysis From the ACTIVE Phase 3 Trial.

CONTEXT: Abaloparatide is a US Food and Drug Administration-approved parathyroid hormone-related peptide analog for treatment of osteoporosis in postmenopausal women at high risk of fracture. OBJECTIVES: We assessed the cardiovascular safety profile of abaloparatide. DESIGN: Review of heart rate (HR), blood pressure (BP), and cardiovascular-related adverse events (AEs), including major adverse cardiovascular events (MACEs) and heart failure (HF) from: (a) ACTIVE (NCT01343004), a phase 3 trial that randomized 2463 postmenopausal women with osteoporosis to abaloparatide, teriparatide, or placebo for 18 months; (b) ACTIVExtend (NCT01657162), where participants from the abaloparatide and placebo arms received alendronate for 2 years; and (c) a pharmacology study in 55 healthy adults. RESULTS: Abaloparatide and teriparatide transiently increased HR relative to placebo. Following first dose, mean (standard deviation [SD]) HR change from pretreatment to 1 hour posttreatment was 7.9 (8.5) beats per minute (bpm) for abaloparatide, 5.3 (7.5) for teriparatide, and 1.2 (7.1) for placebo. A similar pattern was observed over subsequent visits. In healthy volunteers, HR increase resolved within 4 hours. The corresponding change in mean supine systolic and diastolic BP 1 hour posttreatment was -2.7/-3.6 mmHg (abaloparatide), -2.0/-3.6 (teriparatide), and -1.5/-2.3 (placebo). The percentage of participants with serious cardiac AEs was similar among groups (0.9%-1.0%). In a post hoc analysis, time to first incidence of MACE + HF was longer with abaloparatide (P = 0.02 vs placebo) and teriparatide (P = 0.04 vs placebo). CONCLUSIONS: Abaloparatide was associated with transient increases in HR and small decreases in BP in postmenopausal women with osteoporosis, with no increase in risk of serious cardiac AEs, MACE, or HF.