A Single Infusion of Zoledronate in Postmenopausal Women Following Denosumab Discontinuation Results in Partial Conservation of Bone Mass Gains

Discontinuation of denosumab is associated with a rapid return of bone mineral density (BMD) to baseline and an increased risk of multiple vertebral fractures. No subsequent treatment regimen has yet been established for preventing either loss of BMD or multiple vertebral fractures after denosumab discontinuation. The aim of this 8-year observational study was to investigate the effect of a single zoledronate infusion, administered 6 months after the last denosumab injection, on fracture occurrence and loss of BMD. We report on 120 women with postmenopausal osteoporosis who were treated with 60 mg denosumab every 6 months for 2 to 5 years (mean duration 3 years) and then 5 mg zoledronate 6 months after the last denosumab injection. All patients were evaluated clinically, by dual-energy X-ray absorptiometry (DXA) and vertebral fracture assessment (VFA), before the first and after the last denosumab injection and at 2.5 years (median) after denosumab discontinuation. During this off-treatment period, 3 vertebral fractures (1.1 per 100 patient-years) and 4 nonvertebral fractures (1.5 per 100 patient-years) occurred. No patients developed multiple vertebral fractures. Sixty-six percent (confidence interval [CI] 57% to 75%) of BMD gained with denosumab was retained at the lumbar spine and 49% (CI 31% to 67%) at the total hip. There was no significant difference in the decrease of BMD between patients with BMD gains of >9% versus <9% while treated with denosumab. Previous antiresorptive treatment or prevalent fractures had no impact on the decrease of BMD, and all bone loss occurred within the first 18 months after zoledronate infusion. In conclusion, a single infusion of 5 mg zoledronate after a 2- to 5-year denosumab treatment cycle retained more than half of the gained BMD and was not associated with multiple vertebral fractures, as reported in patients who discontinued denosumab without subsequent bisphosphonate treatment. © 2020 American Society for Bone and Mineral Research.     

Progression of Rebound-Associated Vertebral Fractures Following Denosumab Discontinuation Despite Reinstitution of Treatment: Suppressing Increased Bone Turnover May Not Be Enough

Rebound-associated vertebral fractures (RAVFs) could occur in a minority of the patients who discontinue denosumab. In such patients, denosumab is often reinstituted to rapidly suppress bone turnover and avert the risk of additional fractures. Herein we report the cases of 2 patients who sustained RAVFs, and in whom resuming denosumab treatment did not avert the occurrence of new RAVFs a few months later, despite the suppression of bone turnover markers. It seems that denosumab reinstitution cannot completely eliminate the risk of new RAVFs and that the rebound of bone turnover may not be the sole mechanism to explain this phenomenon.     

Bone Mass Gains After One Denosumab Injection Followed by Zoledronate

Denosumab discontinuation can lead to bone loss despite subsequent bisphosphonate therapy. This bone loss is more severe in patients treated with denosumab for longer than 3 years. We aimed to evaluate the bone mass changes after only a single denosumab injection followed by zoledronate administration. We screened all of our patients who received a single denosumab injection and who were included in the osteoporosis register from the Swiss Society of Rheumatology between August 1, 2010, and January 31, 2022. This case series assessed the outcome of patients who were consecutively treated with one denosumab injection followed by a single infusion of zoledronate 6 months later. Bone mineral density (BMD) and bone turnover markers (BTM) changes were analysed before therapy and 18 months later. Percentage BMD changes and T-scores were compared with those of registered patients who received 2.5 years of denosumab treatment and one subsequent infusion of zoledronate. Thirty-two patients (31 female, 1 male) received a single denosumab injection and one zoledronate infusion 6 months later. BTM decreased significantly in this period (p = 0.035). Percentage BMD changes from baseline to 1 year after zoledronate treatment were 7.6% [IQR 3.2, 9.4] at the lumbar spine, 3.5% [1.8, 5.9] at the total hip and 4.6% [1.3, 6.0] at the femoral neck. In contrast, percentage changes from baseline in 110 patients with 2.5 years of denosumab treatment and one zoledronate infusion were 5.6% [3.0, 9.1], 2.3% [0.2, 4.9] and 2.3% [?0.9, 4.7], respectively. Differences between the 2 groups were significant at the lumbar spine (p = 0.014), total hip (p = 0.010) and femoral neck (p = 0.010).A single denosumab injection followed by zoledronate led to a remarkable gain of BMD at the lumbar spine and hip within a short time. This observation could help to identify a new short treatment sequence for patients with osteoporosis.     

Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo‐Controlled FREEDOM Trial and Its Extension

Denosumab reduces bone resorption and vertebral and nonvertebral fracture risk. Denosumab discontinuation increases bone turnover markers 3 months after a scheduled dose is omitted, reaching above‐baseline levels by 6 months, and decreases bone mineral density (BMD) to baseline levels by 12 months. We analyzed the risk of new or worsening vertebral fractures, especially multiple vertebral fractures, in participants who discontinued denosumab during the FREEDOM study or its Extension. Participants received ≥2 doses of denosumab or placebo Q6M, discontinued treatment, and stayed in the study ≥7 months after the last dose. Of 1001 participants who discontinued denosumab during FREEDOM or Extension, the vertebral fracture rate increased from 1.2 per 100 participant‐years during the on‐treatment period to 7.1, similar to participants who received and then discontinued placebo (n = 470; 8.5 per 100 participant‐years). Among participants with ≥1 off‐treatment vertebral fracture, the proportion with multiple (>1) was larger among those who discontinued denosumab (60.7%) than placebo (38.7%; p = 0.049), corresponding to a 3.4% and 2.2% risk of multiple vertebral fractures, respectively. The odds (95% confidence interval) of developing multiple vertebral fractures after stopping denosumab were 3.9 (2.1–7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, and 1.6 (1.3–1.9) times higher with each additional year of off‐treatment follow‐up; among participants with available off‐treatment total hip (TH) BMD measurements, the odds were 1.2 (1.1–1.3) times higher per 1% annualized TH BMD loss. The rates (per 100 participant‐years) of nonvertebral fractures during the off‐treatment period were similar (2.8, denosumab; 3.8, placebo). The vertebral fracture rate increased upon denosumab discontinuation to the level observed in untreated participants. A majority of participants who sustained a vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with greatest risk in participants with a prior vertebral fracture. Therefore, patients who discontinue denosumab should rapidly transition to an alternative antiresorptive treatment. Clinicaltrails.gov : NCT00089791 (FREEDOM) and NCT00523341 (Extension). © 2017 American Society for Bone and Mineral Research.     

Zoledronate for the Prevention of Bone Loss in Women Discontinuing Denosumab Treatment. A Prospective 2-Year Clinical Trial

Cessation of denosumab treatment is associated with increases in bone turnover above baseline values and rapid bone loss. We investigated the efficacy of zoledronate to prevent this bone loss in women with postmenopausal osteoporosis who were treated with denosumab (mean duration 2.2 years) and discontinued treatment after achieving osteopenia. Women were randomized to receive a single 5-mg infusion of zoledronate (ZOL) (n = 27) or two additional 60-mg injections of denosumab (Dmab) (n = 30). Both groups were followed for a total period of 24 months. At 24 months lumbar spine–bone mineral density (LS-BMD) was not different from baseline in the ZOL group, but decreased in the Dmab group by (mean ± SD) 4.82% ± 0.7% (p < 0.001) from the 12-month value; the difference in BMD changes between the two groups, the primary endpoint of the study, was statistically significant (p = 0.025). Results of femoral neck (FN)-BMD changes were similar. ZOL infusion was followed by small but significant increases in serum procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) during the first year and stabilization thereafter. In the Dmab group, bone turnover marker values did not change during the first 12 months but increased significantly at 15 months and in the majority of women these remained elevated at 24 months. Neither baseline nor 12-month bone turnover marker values were associated with BMD changes in either group of women. In the Dmab group, three patients sustained vertebral fractures (two patients multiple clinical, one patient morphometric) whereas one patient in the ZOL group sustained clinical vertebral fractures 12 months after the infusion. In conclusion, a single intravenous infusion of ZOL given 6 months after the last Dmab injection prevents bone loss for at least 2 years independently of the rate of bone turnover. Follow-up is recommended, because in a few patients ZOL treatment might not have the expected effect at 2 years. © 2019 American Society for Bone and Mineral Research.     

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

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

Osteoporosis Treatment: When to Discontinue and When to Re-start

A number of effective therapies for the treatment of osteoporosis have become available in recent years. However, uncertainty exists regarding their long-term use and effectiveness. Bisphosphonate treatment, unlike hormone replacement, denosumab or teriparatide, is associated with benefits extended even after treatment discontinuation. The extended benefits are most apparent for alendronate (ALN) and zoledronate (ZOL). A drug holiday might be considered in patients at low-moderate risk and who have been fully compliant with treatment, and who have had a response to treatment. In patients at low-moderate risk of fractures the decision to consider a drug holiday should be balanced also with the safety profile of each treatment.     

Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment.

A follow-up in 1262 women was conducted after the discontinuation of teriparatide. The hazard ratio for combined teriparatide group (20 and 40 microg) for the 50-month period after baseline was 0.57 (p = 0.002), suggesting a sustained effect in reducing the risk of nonvertebral fragility fracture. INTRODUCTION: Treatment with teriparatide [rhPTH(1-34)] 20 and 40 microg once-daily subcutaneous dosing significantly reduced the risk of nonvertebral fragility fractures over a median exposure of 19 months. MATERIALS AND METHODS: All participants in the Fracture Prevention Trial were invited to participate in a follow-up study. Prior treatment assignments were revealed, and patients were able to receive osteoporosis treatments without restriction. RESULTS: Approximately 60% of the 1262 patients received an osteoporosis treatment at some time during follow-up, with greater use in the former placebo group than in the combined former teriparatide group (p < 0.05). The hazard ratios for nonvertebral fragility fractures in each teriparatide group relative to placebo were statistically significant for the 50-month period including treatment and follow-up (p < 0.03). In the follow-up period, the hazard ratio was significantly different between the 40 mug and combined groups versus placebo but not for the 20 microg group versus placebo. However, the 20 and 40 microg groups were not different from each other. Kaplan-Meier analysis of time to fracture showed that the fracture incidence in the former placebo and teriparatide groups diverged during the 50-month period including teriparatide treatment and follow-up (p = 0.009). Total hip and femoral neck BMD decreased in teriparatide-treated patients who had no follow-up treatment; BMD remained stable or further increased in patients who received a bisphosphonate after teriparatide treatment. CONCLUSIONS: While the study design is observational, the results support a sustained effect of teriparatide in reducing the risk of nonvertebral fragility fractures up to 30 months after discontinuation of treatment.     

Patterns of Teriparatide and Sequential Antiresorptive Agent Treatment Among Elderly Female Medicare Beneficiaries

The 2020 American Association of Clinical Endocrinologists guidelines for assessing osteoporosis among postmenopausal women stratified postmenopausal women with osteoporosis to “high” and “very-high” fracture risk categories and recommended anabolic agents as initial therapy followed by an antiresorptive agent. Switching the order can blunt the effect of anabolic agents, and failing to follow with an antiresorptive can lead to loss of bone generated by the anabolic agent. It would be helpful to understand the real-world prescribing patterns of anabolic agents. Using the 2010–2015 Medicare 100% osteoporosis database, we assessed patient profiles, teriparatide prescribers, persistence of teriparatide therapy, and antiresorptive agent use after teriparatide discontinuation among elderly women who initiated teriparatide from 2011 to 2013. This study included 14,786 patients. In the year before teriparatide initiation, 30.0% of them had a fracture, 67.6% had a dual energy x-ray absorptiometry scan, 74.4% had a diagnosis of osteoporosis, and 47.9% used antiresorptive agents (non-naïve teriparatide users). Among those who had fractures, 49.4% initiated teriparatide within 3 months postfracture. Teriparatide was prescribed for 37% of users by primary care doctors, 19% by rheumatologists, 13% by endocrinologists, and 7.0% by orthopedists. Median time of teriparatide use was 7.2 months. After teriparatide discontinuation, 40.8% switched to antiresorptive agents (31.9% among naïve teriparatide users, 50.5% among non-naïve users). Among switchers, 42.5% switched within 60 days, 50.5% switched to denosumab, and 31.6% switched to oral bisphosphonates. This study of real-world prescribing data found that about half of teriparatide users switched from an antiresorptive agent, and less than half switched to antiresorptive agents after teriparatide discontinuation. Persistence of teriparatide use was suboptimal. In the management of postmenopausal osteoporosis, increasing the persistence of teriparatide use and improving the appropriate treatment sequence of anabolic and antiresorptive drugs are critical to maximizing gains in bone mass, providing the greatest protection against fractures. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Efficacy of Zoledronic Acid in Maintaining Areal and Volumetric Bone Density After Combined Denosumab and Teriparatide Administration: DATA-HD Study Extension

Combined teriparatide and denosumab rapidly and substantially increases bone mineral density (BMD) at all anatomic sites. Discontinuation of denosumab however, results in high-turnover bone loss and increased fracture risk. The optimal way to prevent this bone loss remains undefined. This study is a preplanned extension of the DATA-HD study, where postmenopausal women with osteoporosis were randomized to receive 9 months of either 20 μg or 40 μg of teriparatide daily overlapping with denosumab (60 mg administered at months 3 and 9). At the completion of this 15-month study, women were invited to enroll in the DATA-HD Extension where they received a single dose of zoledronic acid (5 mg) 24 to 35 weeks after the last denosumab dose. Areal BMD and bone turnover markers were measured at month 27 and 42 (12 and 27 months after zoledronic acid, respectively) and spine and hip volumetric bone density by quantitative CT was measured at month 42. Fifty-three women enrolled in the DATA-HD Extension. At the femoral neck and total hip, the mean 5.6% and 5.1% gains in BMD achieved from month 0 to 15 were maintained both 12 and 27 months after zoledronic acid administration. At the spine, the mean 13.6% gain in BMD achieved from month 0 to 15 was maintained for the first 12 months but modestly decreased thereafter, resulting in a 3.0% reduction (95% CI, −4.0% to −2.0%, p < .0001) 27 months after zoledronic acid. The pattern of BMD changes between months 15 and 42 were qualitatively similar in the 20-μg and 40-μg groups. A single dose of zoledronic acid effectively maintains the large and rapid total hip and femoral neck BMD increases achieved with combination teriparatide/denosumab therapy for at least 27 months following the transition. Spine BMD was also largely, though not fully, maintained during this period. These data suggest that the DATA-HD Extension regimen may be an effective strategy in the long-term management of patients at high risk of fragility fracture. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial.

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

Effects of Combination Denosumab and High-Dose Teriparatide Administration on Bone Microarchitecture and Estimated Strength: The DATA-HD HR-pQCT Study

In postmenopausal women at high risk of fracture, we previously reported that combined denosumab and high-dose (HD; 40 μg) teriparatide increased spine and hip bone mineral density (BMD) more than combination with standard-dose teriparatide (SD; 20 μg). To assess the effects of these combinations on bone microarchitecture and estimated bone strength, we performed high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and distal tibia in these women, who were randomized to receive either teriparatide 20 μg (n = 39) or 40 μg (n = 37) during months 0 to 9 overlapped with denosumab 60 mg s.c. given at months 3 and 9, for a 15-month study duration. The 69 women who completed at least one study visit after baseline are included in this analysis. Over 15 months, increases in total BMD were higher in the HD-group than the SD-group at the distal tibia (5.3% versus 3.4%, p = 0.01) with a similar trend at the distal radius (2.6% versus 1.0%, p = 0.06). At 15 months, cortical porosity remained similar to baseline, with absolute differences of −0.1% and −0.7% at the distal tibia and −0.4% and −0.1% at the distal radius in the HD-group and SD-group, respectively; p = NS for all comparisons. Tibial cortical tissue mineral density increased similarly in both treatment groups (1.3% [p < 0.0001 versus baseline] and 1.5% [p < 0.0001 versus baseline] in the HD-group and SD-group, respectively; p = 0.75 for overall group difference). Improvements in trabecular microarchitecture at the distal tibia and estimated strength by micro-finite element analysis at both sites were numerically greater in the HD-group compared with SD-group but not significantly so. Together, these findings suggest that short-term treatment combining denosumab with either high- or standard-dose teriparatide improves HR-pQCT measures of bone density, microstructure, and estimated strength, with greater gains in total bone density observed in the HD-group, which may be of benefit in postmenopausal women with severe osteoporosis. © 2020 American Society for Bone and Mineral Research (ASBMR).     

The Effect of Zoledronic Acid on Bone Microarchitecture and Strength after Denosumab and Teriparatide Administration: DATA-HD Study Extension

The combination of denosumab and teriparatide is an effective treatment strategy in postmenopausal osteoporosis, though skeletal gains are promptly lost when these agents are discontinued. In the DATA-HD study, we reported that a single dose of zoledronic acid (ZOL) maintains the increases in areal spine and hip bone mineral density (BMD) achieved with this combination for at least 12 months. The capacity of ZOL to maintain corresponding improvements in peripheral volumetric BMD and microarchitecture, however, has not been reported. In the 15-month DATA-HD study, 76 postmenopausal osteoporotic women were randomized to receive 9 months of teriparatide (20-μg or 40-μg daily) overlapped with denosumab (60 mg at months 3 and 9). In the Extension study, 53 participants received a single dose of ZOL (5 mg intravenously) 24–35 weeks after the last denosumab dose. We measured volumetric BMD and microarchitecture at the distal radius and tibia using high-resolution peripheral quantitative computed tomography at months 27 and 42. Despite ZOL administration, total and cortical BMD gradually decreased over 27 months resulting in values similar to baseline at the radius but still significantly above baseline at the tibia. At both sites, cortical porosity decreased to values below pretreatment baseline at month 27 but then increased from month 27 to 42. There were no significant changes in trabecular parameters throughout the 27-month post-ZOL observation period. Stiffness and failure load, at both sites, decreased progressively from month 15 42 though remained above baseline at the tibia. These findings suggest that in contrast to the largely maintained gains in dual-energy X-ray absorptiometry (DXA)-derived spine and hip BMD, a single dose of ZOL was not as effective in maintaining the gains in volumetric peripheral bone density and microarchitecture produced by 15 months of overlapping treatment with denosumab and teriparatide. Alternative therapeutic approaches that can fully maintain improvements in peripheral bone parameters require further study. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized,Double‐Blind,Phase 2, Parallel Group Study

Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased bone mineral density (BMD) in postmenopausal women with low BMD (NCT00896532). Herein, we report the study extension evaluating 24 months of treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women aged 55 to 85 years with a lumbar spine (LS), total hip (TH), or femoral neck T‐score ≤–2.0 and ≥–3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70 mg, 140 mg, 210 mg monthly [QM]; 140 mg Q3M; 210 mg Q3M) for 24 months, or open‐label alendronate for 12 months followed by romosozumab 140 mg QM for 12 months. Eligible participants were then rerandomized 1:1 within original treatment groups to placebo or denosumab 60 mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210 mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210 mg QM, bone formation marker P1NP initially increased after treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; bone resorption marker β‐CTX rapidly decreased after treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, whereas after transition to placebo, P1NP returned to baseline and β‐CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of romosozumab are reversible upon discontinuation and further augmented by denosumab. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.     

Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial

INTRODUCTION: Denosumab is a fully human monoclonal antibody that inhibits receptor activator of nuclear factor-kappa B ligand (RANKL), an essential mediator of osteoclast formation, function, and survival that has been shown to decrease bone turnover and increase bone mineral density (BMD) in treated patients. We assessed the long-term efficacy and safety of denosumab, and the effects of discontinuing and restarting denosumab treatment in postmenopausal women with low bone mass. METHODS: Postmenopausal women with a lumbar spine T-score of -1.8 to -4.0 or proximal femur T-score of -1.8 to -3.5 were randomized to denosumab every 3 months (Q3M; 6, 14, or 30 mg) or every 6 months (Q6M; 14, 60, 100, or 210 mg); placebo; or open-label oral alendronate weekly. After 24 months, patients receiving denosumab either continued treatment at 60 mg Q6M for an additional 24 months, discontinued therapy, or discontinued treatment for 12 months then re-initiated denosumab (60 mg Q6M) for 12 months. The placebo cohort was maintained. Alendronate-treated patients discontinued alendronate and were followed. Changes in BMD and bone turnover markers (BTM) as well as safety outcomes were evaluated. RESULTS: Overall, 262/412 (64%) patients completed 48 months of study. Continuous, long-term denosumab treatment increased BMD at the lumbar spine (9.4% to 11.8%) and total hip (4.0% to 6.1%). BTM were consistently suppressed over 48 months. Discontinuation of denosumab was associated with a BMD decrease of 6.6% at the lumbar spine and 5.3% at the total hip within the first 12 months of treatment discontinuation. Retreatment with denosumab increased lumbar spine BMD by 9.0% from original baseline values. Levels of BTM increased upon discontinuation and decreased with retreatment. Adverse event rates were similar among treatment groups. CONCLUSIONS: In postmenopausal women with low BMD, long-term denosumab treatment led to gains in BMD and reduction of BTM throughout the course of the study. The effects on bone turnover were fully reversible with discontinuation and restored with subsequent retreatment.     

Predictors of Fracture in Older Women With Osteopenic Hip Bone Mineral Density Treated With Zoledronate

A recent analysis has found that during treatment with denosumab, women attaining higher bone densities (BMD) are less likely to have incident fractures. We have reexamined this important question using data from our recent trial of zoledronate in osteopenic women. One thousand women randomized to treatment with zoledronate were followed for 6 years. Of those, 122 sustained fragility fractures during follow-up. Baseline age, nonvertebral fracture history, total hip BMD, and calculated fracture risk were all significantly different between those who had fractures during the study and those who did not. BMDs achieved during the study were higher in those without incident fractures. However, achieved BMDs were very closely related to baseline values (r = 0.93, p < 0.0001). The increase in BMD during zoledronate treatment was not different between those who had incident fractures and those who did not (0.15 < p < 0.78), and change in BMD was not predictive of fracture (univariate logistic regression analysis). Stepwise regression analysis of all baseline variables showed the best independent predictors of fracture to be age (odds ratio [OR] = 1.08, 95% confidence interval [CI] 1.04–1.13, p = 0.0003), baseline spine BMD (OR = 0.81, 95% CI 0.67–0.96, p = 0.016), and history of nonvertebral fracture (OR = 1.69, 95% CI 1.06–2.69, p = 0.028). Addition of change in BMD to this model did not improve its predictive power. If changes in BMD were included in the stepwise regression analysis of baseline variables, they did not emerge as significant predictors of fracture. It is concluded that age, fracture history, and baseline BMD determine the risk of new fractures. Differences in achieved BMD between those who do or do not fracture arise from the close relationship between baseline and achieved BMDs. These findings suggest that targeting any particular BMD during treatment is unlikely to be a useful or valid strategy. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Clinical efficacy of bisphosphonates and monoclonal antibodies on bone mineral density following skeletal fractures

BackgroundBisphosphonates and monoclonal antibodies are drugs primarily developed to inhibit osteoclast-mediated bone resorption and are used to treat an array of skeletal pathologies. Their use is aimed at increasing bone health and therefore reducing fracture risks. The aim of this study was to evaluate the effectiveness of bone protection therapy on improving bone mineral density (BMD) in patients following a fracture.MethodsInclusion criteria consisted of patients who sustained a skeletal fracture and were subsequently commenced on bone protection therapy. Dual-energy X-ray Absorptiometry (DEXA) scans were performed at baseline and following a consented period of drug therapy. Bone health data included T-Scores, Z-Scores, FRAX Major, FRAX Hip and BMD. The clinical effectiveness of four bisphosphonates (alendronate, risedronate, pamidronate and zoledronate) and one monoclonal antibody (denosumab) were evaluated.ResultsA total of 100 patients were included in the study. Overall, bone protection therapy significantly improved Z-score Hip, Z-score Spine, T-score Spine and BMD Spine (p < 0.05). There was a marked difference between drug therapies. Denosumab and zoledronate were associated with the greatest treatment effect size. Alendronate only improved Z-score Spine and Z-score Hip (p < 0.05). Pamidronate and risedronate did not demonstrate any statistically significant improvement across any DEXA parameter.ConclusionOverall, bisphosphonates/monoclonal antibodies confer beneficial effects on bone health as measured by DEXA scans in patients following skeletal fractures. However, the magnitude of improvement varies among the commonly used drugs. Alendronate, zoledronate and denosumab were associated with greatest therapeutic benefit. Bone protection therapy did not improve fracture risk of patients (FRAX scores).     

Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters.

An 18-month randomized double-blind study was conducted in postmenopausal women with osteoporosis to compare the effects of once-daily teriparatide 20 microg with alendronate 10 mg on bone histomorphometry. Biopsies were obtained from 42 patients. Indices of bone formation were significantly higher after 6 or 18 months of teriparatide compared with alendronate treatment. INTRODUCTION: Alendronate and teriparatide increased BMD, assessed by DXA, by different mechanisms of action, supported by changes in biochemical markers of bone turnover. The purpose of this cross-sectional study was to explore the differential effects of these two osteoporosis treatments at the bone tissue level by examining bone histomorphometric parameters of bone turnover after either 6 or 18 months of treatment. MATERIALS AND METHODS: Patients were a cohort from a randomized parallel double-blind study conducted to compare the effects of once-daily teriparatide 20 microg and alendronate 10 mg in postmenopausal women with osteoporosis. Transiliac crest bone biopsies were obtained after tetracycline double labeling from 42 patients treated for 6 months (n = 23) or 18 months (n = 14); 5 additional patients were biopsied from contralateral sides at 6 and 18 months. Biopsy specimens adequate for quantitative analysis were analyzed by 2D histomorphometry from 17 patients at 6 months (teriparatide, n = 8; alendronate, n = 9) and 15 patients at 18 months (teriparatide, n = 8; alendronate, n = 7). Data were analyzed by two-sample tests. RESULTS: Histomorphometric indices of bone formation were significantly and markedly greater in the teriparatide group than in the alendronate group at 6 and 18 months, whereas indices of bone resorption were only significantly greater in the teriparatide group than in the alendronate group at 6 months. Bone formation and activation frequency were significantly lower at 18 months compared with 6 months in the teriparatide group, returning to levels comparable with untreated postmenopausal women. In the teriparatide group, the peak in histomorphometric bone formation indices coincided with peak levels for N-terminal propeptide of type I collagen, a biochemical marker of bone formation. The degree of mineralization was lower at 18 months than at 6 months with treatment in both groups but was not different between groups. CONCLUSIONS: These results confirm the opposite mechanisms of action of teriparatide and alendronate on bone remodeling and confirm the bone formation effect of teriparatide.     

Responses to Treatment With Teriparatide in Patients With Atypical Femur Fractures Previously Treated With Bisphosphonates

If oversuppression of bone turnover explained the association between bisphosphonate use and atypical subtrochanteric femur fractures (AFF), this could be reversed with anabolic treatment such as teriparatide. We conducted a prospective, open‐label study in patients previously treated with bisphosphonates who sustained AFF, examining the response to 24‐month treatment with teriparatide on bone mineral density (BMD), trabecular bone score (TBS), bone turnover markers (BTM), and fracture healing as well as quantitative histomorphometry. We studied 14 patients. Baseline BMD, BTM, and TBS varied widely. On initial bone biopsies, 12 of 14 patients showed tetracycline labels, but mineralizing surface/bone surface was below published normal values in all but 2. Lumbar spine BMD increased significantly at month 24 (6.1% ± 4.3%, p < 0.05 versus baseline), whereas total hip BMD and TBS did not change significantly. Changes in BTM occurred as reported previously for patients without AFF treated with teriparatide after prior bisphosphonate treatment. At month 24, fractures were healed in 6 patients, showed partial healing in 3, were unchanged in 2, and showed nonunion in 1. In a patient with two fractures, the fracture that occurred before teriparatide treatment was reported as healed, but the fracture that occurred while on treatment showed only partial healing. Bisphosphonate‐treated patients who sustain AFF show heterogeneity of bone turnover. Treatment with teriparatide resulted in increases in BTM and lumbar spine BMD, as has been reported for patients without AFF. There was no significant effect of teriparatide on hip BMD, mineralizing surface to bone surface (MS/BS), or TBS and no consistent effect on fracture healing. In the context of a patient who has experienced an AFF after receiving bisphosphonate treatment, therapy with teriparatide for 24 months would be expected to increase BMD and BTM (and probably reduce the risk of fractures resulting from osteoporosis) but should not be relied on to aid in healing of the AFF. © 2017 American Society for Bone and Mineral Research.     

Treatment With Zoledronate Subsequent to Denosumab in Osteoporosis: A 2-Year Randomized Study

Increased bone turnover and rapid bone loss follow discontinuation of denosumab. We investigated the long-term efficacy of zoledronate (ZOL) in maintaining bone mineral density (BMD) after discontinuation of denosumab. In this randomized, open-label, interventional study, we included 61 postmenopausal women and men older than 50 years discontinuing denosumab after 4.6 ± 1.6 years. We administered ZOL 6 months (6 M) or 9 months (9 M) after the last denosumab or when bone turnover had increased (observation group [OBS]). ZOL was readministrated if p-cross-linked C-terminal telopeptide (p-CTX) increased ≥1.26 μg/L or BMD decreased ≥5%. The results after 12 months have previously been published; here we report the outcome after 24 months (ClinicalTrials NCT03087851). Fifty-eight patients completed the study. From 12 to 24 months after the initial ZOL, lumbar spine (LS) BMD was maintained: 0.9 ± 0.9%, 0.4 ± 0.8%, and 0.3 ± 0.7% in the 6 M, 9 M, and OBS groups, respectively (p > .05, no between-group differences). Similarly, total hip (TH) and femoral neck (FN) BMD did not change in any group during year 2. From baseline to 24 months after ZOL, LS BMD decreased by 4.0 ± 0.8%, 4.1 ± 0.8%, and 4.3 ± 1.5% in the 6 M, 9 M, and OBS groups, respectively (p < .001, no between-group differences). Significant bone loss (LS, TH, or FN) was found in all groups 24 months after ZOL: 6 M group: n = 12 (60%), 9 M group: n = 7 (37%), and OBS group: n = 10 (53%). P-CTX did not change significantly during the second year (p > .05, no between-group differences). No patient fulfilled the CTX or fracture criteria for retreatment during year 2; however, 9 patients were retreated at M24 due to BMD loss ≥5%. Two patients sustained a non-vertebral fracture during year 2. Treatment with ZOL subsequent to long-term denosumab did not fully prevent increased bone turnover and bone loss during the first year; however, CTX remained with the reference range and BMD was maintained during the second year. © 2021 American Society for Bone and Mineral Research (ASBMR).