Early Effects of Abaloparatide on Bone Formation and Resorption Indices in Postmenopausal Women With Osteoporosis.

Anabolic osteoporosis drugs improve bone mineral density by increasing bone formation. The objective of this study was to evaluate the early effects of abaloparatide on indices of bone formation and to assess the effect of abaloparatide on modeling-based formation (MBF), remodeling-based formation (RBF), and overflow MBF (oMBF) in transiliac bone biopsies. In this open-label, single-arm study, 23 postmenopausal women with osteoporosis were treated with 80 µg abaloparatide daily. Subjects received double fluorochrome labels before treatment and before biopsy collection at 3 months. Change in dynamic histomorphometry indices in four bone envelopes were assessed. Median mineralizing surface per unit of bone surface (MS/BS) increased to 24.7%, 48.7%, 21.4%, and 16.3% of total surface after 3 months of abaloparatide treatment, representing 5.5-, 5.2-, 2.8-, and 12.9-fold changes, on cancellous, endocortical, intracortical, and periosteal surfaces (p < .001 versus baseline for all). Mineral apposition rate (MAR) was significantly increased only on intracortical surfaces. Bone formation rate (BFR/BS) was significantly increased on all four bone envelopes. Significant increases versus baseline were observed in MBF on cancellous, endocortical, and periosteal surfaces, for oMBF on cancellous and endocortical surfaces, and for RBF on cancellous, endocortical, and intracortical surfaces. Overall, modeling-based formation (MBF + oMBF) accounted for 37% and 23% of the increase in bone-forming surface on the endocortical and cancellous surfaces, respectively. Changes from baseline in serum biomarkers of bone turnover at either month 1 or month 3 were generally good surrogates for changes in histomorphometric endpoints. In conclusion, treatment with abaloparatide for 3 months stimulated bone formation on cancellous, endocortical, intracortical, and periosteal envelopes in transiliac bone biopsies obtained from postmenopausal women with osteoporosis. These increases reflected stimulation of both remodeling- and modeling-based bone formation, further elucidating the mechanisms by which abaloparatide improves bone mass and lowers fracture risk. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Abaloparatide in patients with mild or moderate renal impairment: results from the ACTIVE phase 3 trial.

Objective: To evaluate, post hoc, the efficacy and safety of abaloparatide by degree of renal impairment.Methods: ACTIVE was a phase 3, 18-month, randomized, double-blind, active-comparator, placebo-controlled study of postmenopausal women with osteoporosis who received subcutaneous abaloparatide 80 µg, placebo, or open-label teriparatide 20 µg daily. Patients with serum creatinine >2.0 mg/dL or 1.5-2.0 mg/dL with an estimated glomerular filtration rate (eGFR) <37 mL/min, calculated by Cockcroft-Gault formula, were excluded.Results: At baseline, 660 patients had eGFR ≥90 mL/min, 1276 had 60 to ˂90 mL/min, and 527 had <60 mL/min. Older age and lower T-scores were associated with greater renal impairment. Among renal-function subgroups, there were no meaningful changes in bone mineral density, fracture risk reduction, or overall incidence of treatment-emergent adverse events in the active-treatment arms. Anemia, nausea, hypercalcemia, and upper-respiratory-tract infection tended to be more frequent with increasing renal impairment. Hypercalcemia measured by albumin-adjusted serum calcium occurred significantly less frequently with abaloparatide than teriparatide in patients with eGFR <60 mL/min (3.6% versus 10.9%; p = .008) and in the overall ACTIVE safety population (3.4% versus 6.4%; p = .006). Computed tomography scans in 376 patients revealed no evidence of increased renal calcification.Conclusion: Increased exposure to abaloparatide and teriparatide in patients with renal impairment led to no meaningful differences in efficacy or safety. These results support the use of abaloparatide without dosage adjustment in patients with renal impairment, provided those with severe renal impairments are monitored for adverse events.

Quality of life in sarcopenia and frailty.

The reduced muscle mass and impaired muscle performance that define sarcopenia in older individuals are associated with increased risk of physical limitation and a variety of chronic diseases. They may also contribute to clinical frailty. A gradual erosion of quality of life (QoL) has been evidenced in these individuals, although much of this research has been done using generic QoL instruments, particularly the SF-36, which may not be ideal in older populations with significant comorbidities. This review and report of an expert meeting presents the current definitions of these geriatric syndromes (sarcopenia and frailty). It then briefly summarizes QoL concepts and specificities in older populations and examines the relevant domains of QoL and what is known concerning QoL decline with these conditions. It calls for a clearer definition of the construct of disability, argues that a disease-specific QoL instrument for sarcopenia/frailty would be an asset for future research, and discusses whether there are available and validated components that could be used to this end and whether the psychometric properties of these instruments are sufficiently tested. It calls also for an approach using utility weighting to provide some cost estimates and suggests that a time trade-off study could be appropriate.

Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data.

BACKGROUND: Tamoxifen and raloxifene reduce the risk of breast cancer in women at elevated risk of disease, but the duration of the effect is unknown. We assessed the effectiveness of selective oestrogen receptor modulators (SERMs) on breast cancer incidence. METHODS: We did a meta-analysis with individual participant data from nine prevention trials comparing four selective oestrogen receptor modulators (SERMs; tamoxifen, raloxifene, arzoxifene, and lasofoxifene) with placebo, or in one study with tamoxifen. Our primary endpoint was incidence of all breast cancer (including ductal carcinoma in situ) during a 10 year follow-up period. Analysis was by intention to treat. RESULTS: We analysed data for 83,399 women with 306,617 women-years of follow-up. Median follow-up was 65 months (IQR 54-93). Overall, we noted a 38% reduction (hazard ratio [HR] 0·62, 95% CI 0·56-0·69) in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first 5 years of follow-up than in years 5-10 (42%, HR 0·58, 0·51-0·66; p<0·0001 vs 25%, 0·75, 0·61-0·93; p=0·007), but we noted no heterogeneity between time periods. Thromboembolic events were significantly increased with all SERMs (odds ratio 1·73, 95% CI 1·47-2·05; p<0·0001). We recorded a significant reduction of 34% in vertebral fractures (0·66, 0·59-0·73), but only a small effect for non-vertebral fractures (0·93, 0·87-0·99). INTERPRETATION: For all SERMs, incidence of invasive oestrogen (ER)-positive breast cancer was reduced both during treatment and for at least 5 years after completion. Similar to other preventive interventions, careful consideration of risks and benefits is needed to identify women who are most likely to benefit from these drugs. FUNDING: Cancer Research UK.

Long-term raloxifene for postmenopausal osteoporosis.

BACKGROUND: Due to the chronic nature of osteoporosis and the risk of invasive breast cancer, raloxifene 60 mg/day (raloxifene) is intended to be used for long-term treatment (treatment >3 years). SCOPE: We review available information concerning long-term use of raloxifene, present several new analyses, and report new data from patients who underwent iliac crest bone biopsies after 8 years of raloxifene therapy. The most important studies were the Multiple Outcomes of Raloxifene Evaluation (MORE) followed by the Continued Outcomes of Raloxifene Evaluation (CORE). FINDINGS: The primary endpoint in MORE was incidence of vertebral fracture, and the difference between the raloxifene and placebo groups for this endpoint widened during 4 years of therapy, with the relative risk reduction during the fourth year of the study being similar to the relative risk reduction during years 0 to 3 of the study. Continued raloxifene treatment is necessary to preserve bone mineral density (BMD). In MORE, raloxifene lowered markers of bone turnover to a premenopausal reference interval. Biopsies from three patients treated with raloxifene for 8 years showed normal bone and bone cells and double label in all specimens. Invasive breast cancer risk is a clinical consideration in postmenopausal women with osteoporosis, and invasive breast cancer risk reduction was the primary endpoint in CORE. In MORE and CORE, the benefit of raloxifene versus placebo in incidence of invasive breast cancer increased with greater duration of therapy up to 8 years. CONCLUSIONS: The long-term use of raloxifene has been evaluated through changes in fracture risk reduction, BMD, markers of bone turnover, iliac crest bone biopsies, and invasive breast cancer risk reduction.

Effect of Raloxifene on all-cause mortality.

OBJECTIVE: Raloxifene, a selective estrogen receptor modulator, reduces osteoporosis and invasive breast cancer risk but increases risk for venous thromboembolism and fatal stroke in women with or at high risk for coronary heart disease. To assess the risk/benefit of raloxifene as a preventative treatment, we analyzed treatment effects on overall and cause-specific mortality. METHODS: A pooled analysis of mortality data was performed from large clinical trials of raloxifene (60 mg/day) versus placebo, including the Multiple Outcomes of Raloxifene Evaluation/Continuing Outcomes Relevant to Evista studies (7705 postmenopausal osteoporotic women followed for 4 years and a subset of 4011 participants followed for an additional 4 years; 110 deaths) and the Raloxifene Use for the Heart trial (10,101 postmenopausal women with coronary disease or multiple risk factors for coronary disease followed for 5.6 years; 1149 deaths). Cause of death was assessed by blinded adjudicators. Cox proportional hazards regression models compared mortality by treatment assignment in a pooled analysis of trial data from the Multiple Outcomes of Raloxifene Evaluation/Continuing Outcomes Relevant to Evista and Raloxifene Use for the Heart trials. RESULTS: All-cause mortality was 10% lower among women assigned to raloxifene 60 mg/day versus placebo (relative hazard 0.90; 95% confidence interval, 0.80-1.00; P=.05). Lower overall mortality was primarily due to lower rates of noncardiovascular deaths, especially a lower rate of noncardiovascular, noncancer deaths. CONCLUSIONS: All-cause mortality was 10% lower in pooled analyses among older postmenopausal women receiving raloxifene 60 mg/day compared with placebo, due primarily to a reduction in noncardiovascular, noncancer deaths. The mechanism whereby raloxifene might reduce the risk of noncardiovascular death is unclear.

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

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

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

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

Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34).

BACKGROUND: Recombinant human parathyroid hormone (PTH [1-34]; teriparatide) is a new treatment for postmenopausal osteoporosis that can be systemically administered for the primary purpose of increasing bone formation. Because several studies have described the enhancement of fracture-healing and osteointegration in animals after use of PTH, we sought to critically analyze this skeletal effect. METHODS: Two hundred and seventy male Sprague-Dawley rats underwent standard, closed femoral fractures and were divided into three groups that were administered daily subcutaneous injections of 5 or 30 mug/kg of PTH (1-34) or vehicle (control). The dosing was administered for up to thirty-five days. Groups were further divided into three subgroups and were killed on day 21, 35, or 84 after the fracture. The bones were subjected to mechanical torsion testing, histomorphometric analysis, or microquantitative computed tomography. RESULTS: By day 21, calluses from the group treated with 30 mug of PTH showed significant increases over the controls with respect to torsional strength, stiffness, bone mineral content, bone mineral density, and cartilage volume. By day 35, both groups treated with PTH showed significant increases in bone mineral content and density and total osseous tissue volume, and they demonstrated significant decreases in void space and cartilage volume (p < 0.05). Torsional strength was significantly increased at this time-point in the group treated with 30 mug of PTH (p < 0.05). While dosing was discontinued on day 35, analyses performed after eighty-four days in the group treated with 30 mug of PTH showed sustained increases over the controls with respect to torsional strength and bone mineral density. No change was noted in osteoclast density at the time-points measured, suggesting that treatment with PTH enhanced bone formation but did not induce bone resorption. CONCLUSIONS: These data show that daily systemic administration of PTH (1-34) enhances fracture-healing by increasing bone mineral content and density and strength, and it produces a sustained anabolic effect throughout the remodeling phase of fracture-healing.

Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure.

UNLABELLED: Histomorphometry and microCT of 51 paired iliac crest biopsy specimens from women treated with teriparatide revealed significant increases in cancellous bone volume, cancellous bone connectivity density, cancellous bone plate-like structure, and cortical thickness, and a reduction in marrow star volume. INTRODUCTION: We studied the ability of teriparatide (rDNA origin) injection [rhPTH(1-34), TPTD] to improve both cancellous and cortical bone in a subset of women enrolled in the Fracture Prevention Trial of postmenopausal women with osteoporosis after a mean treatment time of 19 months. This is the first report of a biopsy study after treatment with teriparatide having a sufficient number of paired biopsy samples to provide quantitative structural data. METHODS: Fifty-one paired iliac crest bone biopsy specimens (placebo [n = 19], 20 microg teriparatide [n = 18], and 40 microg teriparatide [n = 14]) were analyzed using both two-dimensional (2D) histomorphometry and three-dimensional (3D) microcomputed tomography (microCT). Data for both teriparatide treatment groups were pooled for analysis. RESULTS AND CONCLUSIONS: By 2D histomorphometric analyses, teriparatide significantly increased cancellous bone volume (median percent change: teriparatide, 14%; placebo, -24%; p = 0.001) and reduced marrow star volume (teriparatide, -16%; placebo, 112%; p = 0.004). Teriparatide administration was not associated with osteomalacia or woven bone, and there were no significant changes in mineral appositional rate or wall thickness. By 3D cancellous and cortical bone structural analyses, teriparatide significantly decreased the cancellous structure model index (teriparatide, -12%; placebo, 7%; p = 0.025), increased cancellous connectivity density (teriparatide, 19%; placebo, - 14%; p = 0.034), and increased cortical thickness (teriparatide, 22%; placebo, 3%; p = 0.012). These data show that teriparatide treatment of postmenopausal women with osteoporosis significantly increased cancellous bone volume and connectivity, improved trabecular morphology with a shift toward a more plate-like structure, and increased cortical bone thickness. These changes in cancellous and cortical bone morphology should improve biomechanical competence and are consistent with the substantially reduced incidences of vertebral and nonvertebral fractures during administration of teriparatide.

Parathyroid hormone as a therapeutic agent.

Recent advances in the use of parathyroid hormone as a therapeutic agent include a controlled trial that assessed vertebral and non-vertebral fracture risk reduction in women, trials in men, and assessment of treatment on cortical and trabecular bone structure. The occurrence of osteosarcoma in long-term toxicology studies in rats is briefly reviewed.

Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy.

Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, raloxifene-treated patients had a statistically significantly lower vertebral fracture risk compared with placebo-treated patients. The decrease in fracture risk with raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with raloxifene therapy are poor predictors of vertebral fracture risk reduction with raloxifene therapy.