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The activins-follistatins-inhibins (AFI) hormonal system affects bone metabolism. Treatments that alter bone metabolism may also alter the AFI molecules. In this non-randomized, open-label, head-to-head comparative study, circulating levels of the AFI system were evaluated in postmenopausal women with osteoporosis treated for 12 mo with either teriparatide (n = 23) or denosumab (n = 22). Τeriparatide treatment increased activin B (P=.01) and activin AB (P=.004) and the ratios activin A/follistatin (P=.006), activin B/follistatin (P=.007), activin AB/follistatin (P<.001), and activin AB/ follistatin-like 3 (FSTL3) (P=.034). The significant P for trend in group × time interactions of activins B and AB and of the ratio activin AB/FSTL3 remained robust after adjustment for BMI and LS BMD but it was lost for activin B after adjustment for previous antiresorptive treatment. The effect of teriparatide on BMD was attenuated when it was adjusted for baseline activins levels or their 12-mo changes. No changes were observed after denosumab treatment. In conclusion, activins B and AB, as well as the ratios of all activins to follistatin and of activin AB to FSTL3 increased with teriparatide treatment, possibly in a compensatory manner. Future studies are needed to study the potentially important role activins may play in bone biology and any associations with the effect of teriparatide on BMD. Clinical Trials identifier: NCT04206618. ClinicalTrials.gov  https://clinicaltrials.gov/search?term=NCT04206618., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months after the last injection in postmenopausal women treated for 1-10 years. Serum TRAcP5b values were not related to time of exposure to denosumab., Purpose: In women with postmenopausal osteoporosis the aetiology of the observed inverse relationship between duration of denosumab (Dmab) therapy and bone loss after its discontinuation is currently unknown. In studies in mice inhibition of RANKL is associated with an increase in osteomorphs and osteoclast precursors that recycle into osteoclasts and may accumulate with time. We hypothesized that longer inhibition of RANKL by Dmab will be followed by the synchronous formation of a larger number of osteoclasts after stopping treatment. To test this hypothesis, we measured serum TRAcP5b, a marker of osteoclast numbers, in postmenopausal women treated with Dmab for different periods of time up to 10 years., Methods: TRAcP5b, C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at 6.0 months ± 15 days after last Dmab injection in 59 women who had received Dmab for 4.0 ± 2.3 years (range 1-10 years). Of these, 38 were treatment naïve (group 1) and 21 had received other treatments prior Dmab (group 2)., Results: Duration of Dmab treatment was not related to serum TRAcP5b values or to TRAcP5b/CTX ratio either in the whole cohort or in each of the two groups separately. In contrast, serum TRAcP5b values were significantly correlated with serum CTX values (r s  = 0.619; p < 0.001), but not with serum P1NP values or BMD at all skeletal sites., Conclusion: Our observations indicate that serum TRAcP5b, measured at 6 months after a Dmab injection, is not a useful early marker for time-dependent increased accumulation of osteoclasts in humans and for identification of patients at risk for a higher rebound increase in bone resorption., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

The long-term effects of zoledronate treatment in women with postmenopausal osteoporosis who stop denosumab therapy when they become osteopenic are not known. In a prospective, randomized, controlled clinical trial we previously reported that a single intravenous infusion of zoledronate 5 mg given to such patients 6 months after the last denosumab injection effectively prevents bone loss in the majority of them for up to 3 years. The study was extended for an additional 2 years and included all 19 patients from one Trial Site of the total 27 patients originally randomized in the zoledronate arm. Baseline characteristics of this cohort treated with denosumab for 2.4 ± 0.2 years were not different from those of the whole initial cohort or from the patients who did not participate in this extension. At the end of 5 years 7 patients had become again osteoporotic requiring additional treatment, 9 remained osteopenic while 3 did not complete the study extension. Thus, more than half of the osteoporotic women who became osteopenic with denosumab treatment and stopped it, maintained the BMD gains 5 years after a single zoledronate infusion with no additional treatment. Whether these results are also applicable to patients treated with denosumab for longer periods remains to be established., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The activins-follistatins-inhibins (AFI) hormonal system is considered to regulate muscle and bone mass. We aimed to evaluate AFI in postmenopausal women with an incident hip fracture., Methods: In this post-hoc analysis of a hospital based case-control study, we evaluated circulating levels of the AFI system in postmenopausal women with a low-energy hip fracture admitted for fixation compared with postmenopausal women with osteoarthritis scheduled for arthroplasty., Results: Circulating levels of follistatin (p = 0.008), FSTL3 (p = 0.013), activin B and AB (both p < 0.001), as well as activin AB/follistatin and activin AB/FSTL3 ratios (p = 0.008 and p = 0.029, respectively) were higher in patients than controls in unadjusted models. Differences for activins B and AB remained after adjustment for age and BMI (p = 0.006 and p = 0.009, respectively) and for FRAX-based risk for hip fracture (p = 0.008 and p = 0.012, respectively) but were lost when 25OHD was added to the regression models., Conclusions: Our data indicate no major changes in the AFI system in postmenopausal women at the time of hip fracture compared to postmenopausal women with osteoarthritis except for higher activin B and AB levels, whose significance, however, was lost when 25OHD was added to the adjustment models., Clinical Trials: Clinical Trials identifier: NCT04206618., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Bone metabolism has been proposed to be affected by the activins-follistatins-inhibins (AFI) hormonal system. We aimed to evaluate AFI in patients with osteoporosis and osteopenia compared with postmenopausal and premenopausal controls., Methods: In this case-control study, circulating levels of the AFI system were evaluated, individually and jointly, between postmenopausal women with osteoporosis (BMD T-score ≤-2.5; n = 25) or osteopenia (BMD T-score >-2.5 and ≤-1; n = 25) and postmenopausal women with normal BMD (T-score >-1.0; n = 25) or premenopausal women with normal BMD (Z-score >-1.0; n = 25), with and without adjustment for potential confounders., Results: In the sum of participants, AFI molecules and their ratios followed an opposite pattern of correlations for age and BMI vs. BMD. In unadjusted models, FSTL3 concentrations were higher, whereas activin B, inhibin A and inhibin B and the ratios of activin B/follistatin and activin B/FSTL3 were lower in the three postmenopausal groups compared with the premenopausal group. Activin A/follistatin and activin AB/follistatin ratios were lower in the osteoporosis group than the other three groups. After adjustment for BMI and age, inhibin B (p = 0.005), and the ratios of activin A/follistatin (p = 0.009), activin B/follistatin (p = 0.040) and activin AB/follistatin (p = 0.003) were lower in the osteoporotic group compared with the other groups. In fully adjusted logistic regression analysis log(inhibin B) (p = 0.041), log(activinA/follistatin) (p = 0.014), log(activinB/follistatin) (p = 0.025) and log(activinAB/follistatin) (p = 0.021), but not FSTL3, remained independently associated with the presence of osteoporosis., Conclusions: Lower inhibin B and higher ratios of activins A, B, and AB to follistatin are associated with lumbar spine BMD and the presence of osteoporosis independently from age or BMI., Competing Interests: Conflict of interest CSM is a consultant of Ansh Laboratories. BK and AK are Ansh Laboratories employees. The rest of the authors have no conflict of interest in relation to the present study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Denosumab discontinuation results in rapid bone loss and increased risk of multiple rebound-associated vertebral fractures (RAVFs). The optimal treatment for patients who have sustained such fractures is currently unknown. We aimed to investigate the bone mineral density (BMD) changes achieved with various regimens in postmenopausal women who had sustained RAVFs after denosumab discontinuation in everyday clinical practice. In this multicenter, retrospective observational study, 39 Greek postmenopausal women from six regional bone centers throughout Greece with RAVFs after denosumab discontinuation were included. We collected BMD and fracture data before and 1 year after treatment with denosumab (n = 20), teriparatide (n = 8), zoledronate (n = 8) or teriparatide/denosumab combination (n = 3). Both lumbar spine (LS)-- and femoral neck (FN)-BMD were preserved with all regimens used. With the exception of zoledronate, a trend towards increase was observed with all regimens in LS-BMD. Three patients sustained additional fractures despite treatment reinstitution (2 with zoledronate and 1 with teriparatide). Among patients with RAVFs following denosumab discontinuation both antiresorptive (zoledronate and denosumab) and anabolic (teriparatide) treatment as well as the combination of denosumab with teriparatide seem to be effective in terms of BMD response., (Copyright © 2021 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Context: Zoledronate is used to prevent bone loss following denosumab discontinuation but its efficacy differs among studies., Objective: To test if the duration of denosumab treatment affects the efficacy of subsequent zoledronate infusion., Methods: This multicenter, prospective cohort study, conducted at 2 Greek and 1 Dutch bone centers, included 47 postmenopausal women (n = 47) who received a single zoledronate infusion 6 months after the last denosumab injection and then were followed for 1 year. Twenty-seven women received ≤ 6 denosumab injections (≤ 6 Group) and 20 received > 6 denosumab injections (> 6 Group). The main outcome measure was changes in lumbar spine (LS) bone mineral density (BMD)., Results: At 12 months LS-BMD values were maintained in the ≤ 6 Group (0.98 ± 0.10 to 0.99 ± 0.9 g/cm2, P = 0.409) but decreased significantly in the > 6 Group (1.0 ± 0.11 to 0.93 ± 0.12 g/cm2, P < 0.001). The percent change of LS-BMD of the ≤ 6 Group (+1.0%) was significantly different (P < 0.001) from the change of the > 6 Group (-7.0%). In the whole cohort, the duration of denosumab treatment was negatively correlated with the percentage change of LS-BMD (rs = -0.669, P < 0.001) but not with the change of femoral neck (FN)-BMD. Bone turnover markers increased in all patients 6 months following zoledronate administration with no difference between the 2 groups., Conclusion: The duration of denosumab treatment significantly affects the efficacy of subsequent zoledronate infusion to maintain BMD gains. Frequent follow-up of patients treated with denosumab longer than 3 years is advisable as additional therapeutic interventions may be needed., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Discontinuation of denosumab treatment is associated with rapid bone loss that could be prevented in many patients by zoledronate (ZOL) infusion given 6 months after the last denosumab injection. The effects, however, of zoledronate administration at a later time point are unknown. We aimed to compare the 1-year effect of ZOL infusion given 6 versus 18 months following the last Dmab injection. In this extension of a previously reported 2-year randomized clinical trial, we included initially treatment-naive postmenopausal women, who became osteopenic after approximately 2.5 years of denosumab therapy, and were subjected to a single ZOL infusion at 6 months (early-ZOL, n = 27) versus 18 months (late-ZOL, n = 15) after the last Dmab injection. Annual changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), and markers of bone turnover (P1NP, CTx) at 6 and 12 months following ZOL infusion were assessed. LS BMD was maintained in both early-ZOL (+ 1.7%) and late-ZOL (+ 1.8%) infusion with no difference between groups (p = 0.949). FN BMD was maintained in early-ZOL (+ 0.1%) and increased in late-ZOL (+ 3.4%) infusion with no difference between groups (p = 0.182). Compared to 6 months after last Dmab injection, the overall LS BMD change of the late-ZOL group (- 3.5%) was significantly different (p = 0.007) from that of the early-ZOL group (+ 1.7%). P1NP and CTx gradually increased in the early-ZOL group, while profoundly decreased and remained suppressed in the late-ZOL infusion. A ZOL infusion 18 months following the last Dmab injection is still useful in terms of BMD maintenance and BTM suppression. However, there is no clear clinical benefit compared to the early infusion, while any theoretical advantage is counterbalanced from the expected bone loss, especially at the LS, and the risk of rebound-associated fractures.Trial Registration: NCT02499237; July 16, 2015.

In postmenopausal women, osteoporosis may coexist with other metabolic diseases, including, but not limited to, obesity, diabetes, nonalcoholic fatty liver disease (NAFLD), dyslipidemia and cardiovascular disease (CVD). This association may lie beyond simple coincidence owing to high prevalence of all these diseases, especially in the aging population, as common pathogenetic mechanisms between them and osteoporosis may exist. In this context, anti-osteoporotic medications may affect the pathogenesis of some of these metabolic diseases; this is an important consideration when selecting the most appropriate medication for osteoporotic patients with coexistent metabolic diseases. Conversely, some current or emerging medications for metabolic diseases adversely affect bone metabolism and, if possible, should be avoided in women with postmenopausal osteoporosis. The main aim of this review is to summarize the evidence on anti-osteoporotic treatment in postmenopausal women with concomitant metabolic diseases, i.e. obesity, diabetes, NAFLD, dyslipidemia and CVD. The secondary aim is to present data on the effect of current or emerging medication for metabolic diseases on bone metabolism of postmenopausal women. Deeper understanding of the underlying links between osteoporosis and metabolic diseases may have clinical implications. However, mechanistic studies are needed to elucidate the potential pathophysiological links, as well as clinical trials in women with postmenopausal osteoporosis coexisting with specific metabolic diseases; these may guide clinical practice in the future for the selection of the best anti-osteoporotic medication for each patient with specific metabolic diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Introduction: In women with postmenopausal osteoporosis denosumab discontinuation is associated with rapid bone loss that could be potentially prevented by a single zoledronate infusion for two years. The longer-term effects, however, of zoledronate treatment are unknown. We aimed to study the effect of a single zoledronate infusion during the third year following denosumab discontinuation, in initially treatment-naive postmenopausal women who became osteopenic after 2.4 ± 0.2 years of denosumab therapy., Methods: We report the 1-year follow-up results of a single arm observational extension of a previously reported 2-year multicenter prospective randomized clinical trial. The primary endpoint of this extension was the change in lumbar spine bone mineral density (LS-BMD); secondary endpoints were changes in femoral neck (FN)-BMD and markers of bone turnover (BTM) during the 3rd year from the zoledronate infusion. Changes are presented as mean and SEM., Results: LS-BMD did not change significantly at year 3 compared to year 2 (-1.35 ± 1.1%, p = 1.00) and compared to baseline (-1.96 ± 1.44%, p = 1.00). FN-BMD values did not change while serum P1NP values decreased and CTX values remained unchanged during the third-year of the follow-up. In 4 of the 23 studied women BMD values returned to the osteoporotic range at 3 years., Conclusions: A single i.v. infusion of zoledronate 5 mg, given 6 months after the last injection of denosumab therapy maintains for three years BMD gains in the majority of patients previously treated with denosumab for an approximate period of 2.5 years. Follow-up of patients is, however, recommended because about one-fifth of treated women will require additional antiosteoporotic treatment., Competing Interests: Declaration of competing interest PM has received lecture fees and research grants from Amgen. SEP has received consulting/speaking fees from Amgen; SAP has nothing to declare; NMA-D has participated in the Dutch denosumab Advisory Board; ADA has received lecture fees from Amgen., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Patients discontinuing or neglecting denosumab treatment are at risk of sustaining rebound-associated vertebral fractures (RAVFs). In everyday clinical practice, conventional X-rays are used to diagnose such events in patients reporting acute back pain., Patients: Herein we report the cases of two patients, in whom magnetic resonance imaging (MRI) depicted more RAVFs or allowed earlier detection of RAVFs compared with conventional X-rays., Conclusion: It seems that, in the setting of RAVFs following denosumab discontinuation, MRI imaging provides better accuracy in the diagnostic process and in the classification assessment compared to conventional X-rays, thus allowing an earlier and clearer picture of the magnitude of spinal damage. This could have an impact on clinical decisions and improve patient's management.

Context: Serum expression of microRNAs (miRs) related to bone metabolism is affected by antiosteoporotic treatment., Objective: To investigate the effect of sequential treatments on miR expression in postmenopausal women with osteoporosis., Design: Observational, open label, nonrandomized clinical trial., Setting: A single-center outpatient clinic., Patients and Interventions: Denosumab (Dmab) was administered for 12 months in 37 women who were treatment-naïve (naïve group) (n = 11) or previously treated with teriparatide (TPTD group) (n = 20) or zoledronate (ZOL group) (n = 6)., Main Outcome Measures: Relative serum expression of miRs linked to bone metabolism at 3 and 6 months of Dmab treatment., Results: Baseline relative expression of miR-21a-5p, miR-23a-3p, miR-29a-3p, and miR-338-3p was higher in the TPTD group, while the relative expression of miR-21a-5p was lower in the ZOL group compared to the naïve group. Dmab decreased the relative expression of miR-21a-5p at 3 months (fold change [FC] 0.43, P < 0.001) and 6 months (FC 0.34, P < 0.001), and miR-338-3p and miR-2861 at 6 months (FC 0.31, P = 0.041; FC 0.52, P = 0.016, respectively) in the whole cohort. In subgroup analyses, Dmab decreased the relative expression of miR-21a-5p, miR-29a-3p, miR-338-3p, and miR-2861 at 3 months (FC 0.13, P < 0.001; FC 0.68, P = 0.044; FC 0.46, P = 0.012; and FC 0.16, P < 0.001, respectively) and 6 months (FC 0.1, P < 0.001; FC 0.52, P < 0.001; FC 0.04, P = 0.006; and FC 0.2, P < 0.001, respectively) only within the TPTD group., Conclusions: TPTD treatment potentially affects the expression of the pro-osteoclastogenic miR-21a-5p and miRs related to the expression of osteoblastic genes RUNX2 (miR23a-3p), COL1 (miR-29a-3p), and HDAC5 (miR-2861), while sequential treatment with Dmab acts in the opposite direction., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction : Since postmenopausal osteoporosis is a chronic, potentially disabling condition requiring long-term treatment, the physician is expected to decide the optimal treatment strategy, e.g. how to use the available osteoanabolic and antiresorptive agents, sequentially or in combination, in the most effective and safe way, based on personalized patient care. Areas covered : Herein, the authors outline clinical data regarding the efficacy and safety of various sequential treatment strategies. More specifically, they compare the efficacy of osteoanabolic agents when they precede or follow antiresorptive treatment, as well as the efficacy of antiresorptives following other antiresorptives. Finally, the authors quote and discuss available evidence regarding the efficacy and safety of the co-administration of osteoanabolics and antiresorptives in comparison with monotherapies. Expert opinion : Initiation with an osteoanabolic agent followed by an antiresorptive seems to be the optimal treatment sequence, at least in patients with severe osteoporosis. Osteoanabolic treatment following antiresorptives seems to lead in more modest responses in bone mineral density (BMD) and bone turnover markers. Combination therapy with teriparatide and denosumab or zoledronate has achieved higher BMD gains compared to each agent alone; however, due to the high cost, combination therapy is rarely compensated. On the contrary, the combination of teriparatide with alendronate results in smaller BMD increases than TPTD monotherapy.

Objectives: Noggin inactivates bone morphogenetic proteins (BMPs), possibly exerting negative effects on the skeleton.We aimed to compare the effect of agents with opposite impact on bone turnover on noggin circulating levels., Methods: In this observational, open label, non-randomized clinical study postmenopausal women with low bone mass were treated with either denosumab (n=30) or teriparatide (n=30). Serum samples were obtained at baseline, three and twelve months after treatment initiation. Prevalent fractures were recorded at baseline and lumbar spine bone mineral density (LS BMD) was measured at baseline and twelve months. Measured parameters included noggin, BMP-2, BMP-4, procollagen type 1 N-terminal propeptide (P1NP) and C-terminal cross-linking telopeptide of type 1 collagen (CTx)., Results: Noggin levels remained unchanged after either denosumab or teriparatide treatment. Baseline noggin levels were not different between women with vs. without previous anti-osteoporotic treatment, or between those with vs. without vertebral or non-vertebral fractures and were not correlated with age or LS BMD. At twelve months, noggin levels were positively correlated with P1NP within the denosumab (r s = 0.47; p=0.014), whereas negatively within the teriparatide group (r s = -0.43; p=0.019)., Conclusions: In postmenopausal women with low bone mass noggin levels were not correlated with bone parameters at any time point, except with P1NP at 12 months, and remained stable with both denosumab and teriparatide treatment.

Introduction : Bazedoxifene (BZD) is a third-generation selective estrogen receptor modulator approved for the treatment of postmenopausal osteoporosis with additional favorable effects in lipids, uterine and breast tissue. Areas covered : In this review, the authors outline clinical data regarding the efficacy, safety, and tolerability of continuous BZD administration up to seven years in randomized, placebo-controlled, phase III clinical trials. Long-term treatment with BZD for postmenopausal osteoporosis is generally safe and well tolerated. BZD achieves small but significant increases in the bone mineral density of the lumbar spine but not the total hip. In addition, BZD reduces significantly the risk of vertebral fractures but not of non-vertebral and hip fractures, with the exception of high fracture risk postmenopausal women in whom BZD significantly reduces non-vertebral fractures. Expert opinion : BZD does not seem to offer significant advantages over the other available antiresorptive agents. However, considering the need for long-term management of osteoporosis, BZD may have a place in the long-term therapeutic planning of the disease.

The most widely used medications for the treatment of osteoporosis are currently bisphosphonates (BPs) and denosumab (Dmab). Both are antiresorptives, thus targeting the osteoclast and inhibiting bone resorption. Dmab achieves greater suppression of bone turnover and greater increases of bone mineral density (BMD) at all skeletal sites, both in naïve and pretreated patients. No superiority on fracture risk reduction has been documented so far. In long-term administration, BPs reach a plateau in BMD response after 2-3 years, especially at the hip, while BMD increases progressively for as long as Dmab is administered. Both BPs and Dmab are generally considered safe, although they have been correlated to rare adverse events, such as osteonecrosis of the jaw and atypical femoral fractures. Dmab should be preferred in patients with impaired renal function. BPs are embedded in the bone, from which they are slowly released during bone remodeling, therefore continuing to act for years after their discontinuation. In contrast, Dmab discontinuation fully and rapidly reverses its effects on bone markers and BMD and increases the risk for fractures; therefore, Dmab discontinuation should be discouraged, especially in previously treatment-naïve patients, regardless of the conventional fracture risk. In case of discontinuation, other treatment, mainly BPs, should immediately follow, although the optimal sequential treatment strategy is yet to be defined. Combination of teriparatide with Dmab or zoledronic acid, but not alendronate, provides increased BMD gains at all sites. In conclusion, both BPs and Dmab are safe and efficient therapeutic options although their particularities should be carefully considered in an individual basis., (© 2018 European Society of Endocrinology.)

Context: Expression of microRNAs (miRs) related to bone metabolism in the serum may be affected by antiosteoporotic treatment., Objective: To investigate the effect of two antiosteoporotic agents with opposite effects on bone metabolism on miR expression profile in the serum., Design: Observational, open label, nonrandomized clinical trial., Setting: The outpatient clinics for Metabolic Bone Diseases of 424 General Military Hospital, Thessaloniki, Greece., Patients and Interventions: Postmenopausal women with low bone mass were treated with either teriparatide (TPTD; n = 30) or denosumab (n = 30) for 12 months., Main Outcome Measures: Changes in the serum expression of selected miRs linked to bone metabolism at 3 and 12 months of treatment. Secondary measurements: associations of measured miRs with changes in bone mineral density (BMD) at 12 months and the bone turnover markers (BTMs) C-terminal cross-linking telopeptide of type I collagen and procollagen type I N-terminal propeptide at 3 and 12 months., Results: We found significantly decreased relative expression of miR-33-3p at 3 months (P = 0.03) and of miR-133a at 12 months (P = 0.042) of TPTD treatment. BMD values at 12 months of TPTD treatment were significantly and inversely correlated with miR-124-3p expression at 3 months (P = 0.008). Relative expression of miR-24-3p and miR-27a was correlated with changes in BTMs during TPTD treatment and of miR-21-5p, miR-23a-3p, miR-26a-5p, miR-27a, miR-222-5p, and miR-335-5p with changes in BTMs during denosumab treatment., Conclusions: Circulating miRs are differentially affected by treatment with TPTD and denosumab. TPTD affects the relative expression of miRs related to the expression of RUNX-2 (miR-33) and DKK-1 gene (miR-133).

Persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium found that persistence with denosumab remains consistently high after 24 months in patients at high risk of fracture., Purpose: Continued persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of clinical practice evaluated medication-taking behavior of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium and factors influencing persistence., Methods: Subcutaneous denosumab (60 mg every 6 months) was assigned according to prescribing information and local guidelines before and independently of enrollment; outcomes were recorded during routine practice for up to 24 months. Persistence was defined as receiving the subsequent injection within 6 months + 8 weeks of the previous injection and adherence as administration of subsequent injections within 6 months ± 4 weeks of the previous injection. Medication coverage ratio (MCR) was calculated as the proportion of time a patient was covered by denosumab. Associations between pre-specified baseline covariates and 24-month persistence were assessed using multivariable logistic regression., Results: The 24-month analyses included 1479 women (mean age 66.3-72.5 years) from 140 sites; persistence with denosumab was 75.1-86.0%, adherence 62.9-70.1%, and mean MCR 87.4-92.4%. No covariate had a significant effect on persistence across all four countries. For three countries, a recent fall decreased persistence; patients were generally older with chronic medical conditions. In some countries, other covariates (e.g., older age, comorbidity, immobility, and prescribing reasons) decreased persistence. Adverse drug reactions were reported in 2.3-6.9% patients., Conclusions: Twenty-four-month persistence with denosumab is consistently high among postmenopausal women in Europe and may be influenced by patient characteristics. Further studies are needed to identify determinants of low persistence.

Objective: To test the hypothesis that rebound of bone remodeling is responsible for clinical vertebral fractures reported in a few patients with osteoporosis after cessation of denosumab treatment., Design: In this case-control study we compared clinical and biochemical characteristics of postmenopausal women with clinical vertebral fractures 8-16 months after the last injection of denosumab (Dmab/Fx+, n  = 5) with those of treatment-naïve women with such fractures (Fx+, n  = 5). In addition, 5 women who discontinued denosumab treatment but did not sustain vertebral fractures 18-20 months after the last injection were studied (Dmab/Fx-, n  = 5)., Methods: We measured serum microRNAs, gene expression of mRNAs of factors regulating formation and activity of osteoclasts and biochemical markers of bone and mineral metabolism. In Dmab/Fx+ and Fx+ women, blood was taken 4-8 weeks after the fracture., Results: Compared to Fx+ women, Dmab/Fx+ women had higher serum P1NP and CTx levels, and significantly lower serum miR-503 and miR-222-2 that downregulate osteoclastogenesis and osteoclast activity, and higher RANK (13-fold) and CTSK (2.6-fold) mRNA. The respective values of Dmab/Fx- women were in the same direction as those of Dmab/Fx+ women but of a lesser magnitude., Conclusions: Bone fragility in women with clinical vertebral fractures after stopping denosumab therapy is pathophysiologically different from that of treatment-naïve women with osteoporosis and clinical vertebral fractures and it is associated with upregulation of markers of osteoclast formation and activity. The small number of women with this rare event studied is a limitation., (© 2017 European Society of Endocrinology.)

Background: Circulating microRNAs (miRs) are currently being investigated as novel biomarkers for osteoporosis and osteoporotic fractures., Aim: The aim of this study was to investigate serum levels of specific microRNAs, known regulators of bone metabolism, in postmenopausal women with low bone mass and with or without vertebral fractures (VFs)., Methods: For the analysis, 14 miRs were isolated from the serum of 35 postmenopausal women with low bone mass and with at least one moderate VF and 35 postmenopausal women with low bone mass without fractures. Thirty postmenopausal women with normal BMD values and no history of fractures served as controls. Main outcome parameters were changes in the expression of selected miRs in the serum of patient population and compared with controls., Results: From the 14 miRs that were selected, we identified 5 miRs, namely miR-21-5p, miR-23a, miR-29a-3p, miR-124-3p and miR-2861 that were significantly deregulated in the serum of patients with low bone mass compared with controls. Serum miR-124 and miR-2861 were significantly higher, whereas miR-21, miR-23 and miR-29 were lower in patients compared with controls. In a sub-group analysis of the patient population, the expression of miR-21-5p was significantly lower among osteoporotic/osteopenic women with VFs, showing 66% sensitivity and 77% specificity in distinguishing women with a vertebral fracture., Conclusion: This study identifies a differential expression pattern of miR-21-5p in the serum of women with low BMD and VFs., (© 2017 European Society of Endocrinology.)

Unlabelled: Denosumab and zoledronic acid are potent antiresorptives. In this study in patients pre-treated with zoledronic acid, denosumab achieved similar increases with zoledronic acid in lumbar spine BMD despite the more prominent reduction of bone turnover markers. Denosumab reversibly reduced endogenous RANKL., Introduction: We aimed to compare yearly changes in lumbar spine (LS) bone mineral density (BMD), bone turnover markers, free soluble receptor activator of nuclear factor kappaB ligand (sRANKL) and sclerostin levels between denosumab and zoledronic acid., Methods: Postmenopausal women with low bone mass previously treated with zoledronic acid for 1 year were assigned to denosumab injection (n = 32) or zoledronic acid infusion (n = 26). Procollagen type 1 N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTx), sRANKL, and sclerostin levels were measured in serum samples obtained at baseline and 3, 6, and 12 months after denosumab injection or zoledronic acid infusion. LS BMD was measured at baseline and 12 months., Results: The mean LS increase was 4.5 and 4.4% with denosumab and zoledronic acid, respectively (p = 0.560). Denosumab caused a larger decrease in CTx at 3 months (p < 0.001) and P1NP at 3 (p < 0.001), 6 (p = 0.021), and 12 months (p = 0.042). Denosumab significantly decreased sRANKL by 87.4% at 3 months (p < 0.001). Sclerostin levels were not changed with either intervention (p = 0.162 and p = 0.214, respectively)., Conclusions: In patients previously treated with zoledronic acid, denosumab reduces bone turnover more than zoledronic acid, but the increases in LS BMD are comparable. Furthermore, denosumab administration results in reversible inhibition of the metabolically significant endogenous free soluble RANKL levels. Serum sclerostin is not affected by either agent.

Purpose: To compare denosumab-induced changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), bone markers and free soluble receptor activator of nuclear factor kappaB ligand (sRANKL) between treatment naïve postmenopausal women with low bone mass (naïve group) and those who were previously treated with a single zoledronic acid infusion (post-Zol group)., Procedures: Procollagen type 1N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTx) and sRANKL levels were measured in serum samples obtained at baseline and 3, 6 and 12months after denosumab initiation. LS and FN BMD were measured at baseline and 12months., Results: LS and FN BMD increased significantly in both naïve and post-Zol group (p<0.001 and p=0.025 vs. p<0.001 and p=0.017, respectively). Despite the higher P1NP and CTx levels in naïve patients at baseline (both p<0.001), denosumab caused comparable decreases in both groups at month 3, which returned to post-Zol group baseline levels at month 6 and 12 in all patients. Similarly, sRANKL levels decreased significantly at month 3 in both groups and returned to baseline levels at months 6 and 12., Conclusions: In patients previously treated with zoledronic acid, sequential denosumab treatment is effective in terms of BMD increases and bone turnover suppression. Despite the lower baseline levels in patients pre-treated with zoledronic acid, bone markers are similarly decreased in both groups following denosumab administration and maintain their reversibility. Denosumab reversibly suppresses endogenous free sRANKL levels in both naïve and zoledronic acid pre-treated patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The evaluation of circulating semaphorin-4D (sema4D) and plexin-B1 in postmenopausal women with low bone mass and the effect of antiresorptive or osteoanabolic treatment., Methods: Serum samples were obtained from postmenopausal women with low bone mass at baseline and 3 months after zoledronic acid infusion (n = 30), denosumab injection (n = 30) or teriparatide initiation (n = 28) and from controls matched for age, age at menopause and body mass index (n = 30) at the same time points., Main Outcome Measures: Circulating sema4D and plexin-B1., Results: Circulating sema4D increased following denosumab (p = 0.026), whereas decreased following teriparatide (p = 0.013). Sema4D/plexin-B1 ratio increased following denosumab (p = 0.004). At baseline, sema4D and plexin-B1 levels were higher in patients pre-treated with bisphosphonates compared to naïve ones (p < 0.001 and p = 0.001, respectively). In bivariate correlations sema4D was inversely correlated with serum carboxyterminal telopeptide of type 1 collagen (rs -0.282, p = 0.002), intact parathyroid hormone (rs -0.388, p < 0.001) and 25(OH)D (rs -0.316, p < 0.001), whereas there was a trend towards correlation with lumbar spine bone mineral density (rs -0.191, p = 0.053)., Conclusions: Sema4D levels are independently associated with previous bisphosphonate treatment, intact parathyroid hormone and 25(OH)D levels. Denosumab and teriparatide seem to exert an opposite effect on circulating sema4D levels. Further studies are needed to evaluate whether sema4D mediates the coupling effect that occurs following both antiresorptive and osteoanabolic treatment.

Unlabelled: In vitro data suggest that myokine irisin may affect bone metabolism by promoting osteoblast differentiation while inhibiting osteoclast differentiation. In this study, circulating irisin levels were associated with previous osteoporotic fractures but not with bone mass and were not affected by denosumab or teriparatide treatment for 3 months., Introduction: This study aimed to evaluate predictors of circulating irisin in postmenopausal women with low bone mass and to assess a potential effect of denosumab or teriparatide treatment for 3 months., Methods: Serum samples for irisin measurement were obtained from (a) postmenopausal women with low bone mass (lumbar spinal [LS] or femoral neck [FN] bone mineral density [BMD] T-score ≤-2.0) and their age-matched controls at baseline and 3 months after denosumab (Dmab) injection (Dmab group, n = 50; Dmab control group, n = 25) and (b) women with more severe disease (LS or FN BMD T-score ≤-2.8) and their age-matched controls at the above-mentioned time points after teriparatide (TPTD) initiation (TPTD group, n = 25; TPTD control group, n = 25)., Results: At baseline, irisin levels were inversely correlated with age (partial coefficient (r p ) = -0.24; p = 0.009), parathyroid hormone (PTH) (r p  = -0.30; p = 0.001), and creatinine (r p  = -0.23; p = 0.016) in univariate analysis, and were lower in women with (n = 26; 41.6 ± 2.7 ng/dL) than without previous osteoporotic fracture(s) (n = 99; 51.0 ± 1.6 ng/dL; p = 0.007). In multiple linear regression, previous osteoporotic fracture(s) and PTH were independently negatively associated with irisin [p = 0.04, CI -16.1 to -0.4 and p = 0.002, CI -0.3 to -0.07, respectively], but only the association with PTH remained after controlling for creatinine levels. Serum irisin levels were not different between women with or without low bone mass and were not affected by either Dmab or TPTD treatment for 3 months., Conclusions: Circulating irisin levels were associated with previous osteoporotic fracture(s); whether this association is independent or is due to confounding by lower muscle mass, potentially reflected by lower creatinine levels, remains to be fully clarified.

Objective: Denosumab is a new potent antiresorptive treatment of osteoporosis that can potentially induce a compensatory increase in parathyroid hormone (PTH) levels. We aimed to evaluate the alteration of PTH 1 and 6 months after denosumab's administration with different regimens of calcium and vitamin D (Ca/D) supplementation., Design: Prospective, multicenter, study in a relatively small, heterogeneous sample of postmenopausal women followed for 6 months., Patients: Forty seven postmenopausal women followed in 2 outpatient clinics, requiring onset or continuation of osteoporosis treatment. We administered 1 g calcium carbonate and 800 IU cholecalciferol daily for 6 months (Group A) or the double dose for the first month followed by the 1 g/800 IU Ca/D regimen for the next 5 months (Group B)., Measurements: Parathyroid hormone (PTH) alterations between and within groups, and their associations with serum Ca and bone markers., Results: Parathyroid hormone (PTH) levels were significantly higher at month 1 and 6 only in Group A; Ca levels were significantly decreased at month 1 and returned to baseline values at month 6 within the same Group. The mean per cent change between month 1 and baseline for PTH [Δ(PTH1-0 )] was significantly higher in Group A than B (63·5% ± 28·2% vs -3·0% ± 4·7%, P = 0·029). Δ(PTH1-0 ) was correlated with the reciprocal Δ-changes of Ca (rs  = -0·610; P = 0·002) and collagen type I C-terminal telopeptide (rs  = -0·697; P = 0·003) only in Group A., Conclusions: An increase in PTH should be expected, at least following the first administration of denosumab in common clinical practice. The effect of this compensatory onsequence in bone metabolism warrants further investigation., (© 2013 John Wiley & Sons Ltd.)

Unlabelled: Activin-A is expressed in bone and seems to regulate osteoclastogenesis. In this study, serum activin-A was increased in postmenopausal women with low bone mass and was positively correlated to age and negatively to lumbar spinal bone mineral density (BMD). Serum activin-A levels did not change 3 months after zoledronic acid infusion., Introduction: The aims of the study were to evaluate prospectively the circulating activin-A levels in postmenopausal women with low bone mass and explore possible correlations with clinical and laboratory data, as well as the 3-month effect of zoledronic acid infusion., Methods: Postmenopausal women with low bone mass assigned to receive zoledronic acid infusion (Patients, n = 47) and age-matched, postmenopausal women with normal bone mass (Controls, n = 27) were recruited on an outpatient basis. Main outcome measurement was serum activin-A levels., Results: Serum activin-A was higher in patients at baseline compared to controls (p < 0.001) and activin-A in the serum of patients and controls was positively correlated with age (Spearman's coefficient of correlation [rs] = 0.325; p = 0.005) and negatively with lumbar spinal (LS) BMD (rs = -0.425; p < 0.001). In multiple linear regression analysis, only age (B = 8.93; 95 % CI = 4.39-13.46; p < 0.001) was associated with serum activin-A levels at baseline, independent from group (patients or controls), previous anti-osteoporotic treatment, LS BMD and follicle-stimulating hormone. Circulating activin-A levels were not affected 3 months after zoledronic acid infusion., Conclusions: Serum activin-A is increased in postmenopausal women with low bone mass compared with postmenopausal women with normal bone mass and is positively correlated to age and negatively to LS BMD.

Objective: Patients treated with intravenous zoledronate frequently experience an acute phase reaction (APR) characterized by flu-like symptoms and increased levels of inflammatory cytokines. We aimed to define the role of various cytokines/adipocytokines in zoledronate-induced APR and develop a prognostic model for its prediction., Patients and Measurements: Fifty-one postmenopausal women with low bone mass were subjected to zoledronate intravenous infusion. Patients were divided into those who experienced APR (APR+) and those who did not (APR-). APR was clinically defined by body temperature and the visual analogue pain scale for musculoskeletal symptoms. White blood cell count, leucocytic subpopulations, C-reactive protein, interleukin-6, tumour necrosis factor-alpha, visfatin, resistin and leptin were measured before and 48 h following the infusion. The quantitative insulin sensitivity check index (QUICKI) and homoeostasis model of assessment - insulin resistance (HOMA-IR) were calculated to assess insulin sensitivity and resistance, respectively., Results: (APR+) patients were younger and had lower baseline visfatin and higher baseline lymphocytes and phosphate compared with APR- patients. QUICKI decreased and HOMA-IR increased in APR+ patients while remained unchanged in APR- patients. In binary logistic regression analysis, a model containing previous bisphosphonate treatment, age, body mass index, lymphocytes and visfatin, which predicted zoledronate-induced APR with 82·1% sensitivity and 73·9% specificity, was selected. In this model, lymphocytes (P = 0·010) and visfatin (P = 0·029) at baseline could independently predict APR., Conclusions: Zoledronate-induced APR is associated with serum increases of pro-inflammatory cytokines and an increase of insulin resistance. Patients with higher lymphocytes and lower visfatin levels at baseline are at higher risk for APR., (© 2012 Blackwell Publishing Ltd.)

Unlabelled: Sclerostin is expressed by osteocytes and inhibits bone formation by osteoblasts. In this study, serum sclerostin was positively correlated with either lumbar spinal bone mineral density or T-score. Furthermore, serum sclerostin was increased after 6 months treatment with risedronate, whereas remained unchanged after 6 months teriparatide treatment., Introduction: The primary aim of this study was the evaluation of serum sclerostin levels in postmenopausal women and their association with bone mineral density (BMD) and bone turnover markers. The secondary aim was the evaluation of treatment with either teriparatide (TPTD) or risedronate (RIS) on serum sclerostin levels in women with postmenopausal osteoporosis., Methods: Women with postmenopausal osteoporosis, assigned to receive either TPTD (TPTD group, n = 13) or RIS (RIS group, n = 36) for 6 months, and non-osteoporotic early postmenopausal women (NOEP group, n = 13) were recruited. Main outcome measure was serum sclerostin levels., Results: Serum sclerostin was higher in the NOEP group at baseline compared with either TPTD group (p = 0.007) or RIS group (p = 0.049). Sclerostin was positively correlated with both lumbar spinal (LS) BMD (r = 0.353; p = 0.005) and T-score (r = 0.501; p < 0.001) and negatively correlated with intact parathyroid hormone (r = -0.343; p = 0.024) at baseline. Multiple regression analysis showed that either LS BMD (Beta = 0.653; p = 0.018) or T-score (Beta = 0.711; p = 0.005) were independent predictors of serum sclerostin levels. No significant correlation was observed between serum sclerostin and bone turnover markers or estradiol at baseline. Sclerostin was significantly increased 6 months post-treatment in RIS group (p = 0.002), whereas remained statistically unaffected in the TPTD group., Conclusions: Serum sclerostin is decreased in women with postmenopausal osteoporosis compared with non-osteoporotic early postmenopausal women and is positively correlated to either LS BMD or LS T-score. Furthermore, serum sclerostin was increased after 6 months treatment with RIS, whereas remained essentially unchanged after 6 months TPTD treatment.

The acute-phase response (APR) is frequently observed in patients treated with intravenous (iv) zoledronate (ZOL). We investigated whether a short course of rosuvastatin (ROSU) could attenuate the ZOL--induced APR through blocking the mevalonate pathway at a proximal level. Twenty-eight osteoporotic postmenopausal women with no prior bisphosphonate use (mean age 65.3 ± 1.9 years) were subjected to ZOL iv infusion. Patients were randomly assigned into either a ROSU+ group (n = 12), which received ROSU 10 mg/day starting 5 days before the infusion of ZOL for a total period of 11 days, or a ROSU- group (n = 16), which did not receive ROSU. The visual analog pain scale (VAS) for musculoskeletal symptoms and body temperature was used to define clinically APR. In addition, white blood cell (WBC) count, leukocytic subpopulations, and C-reactive protein (CRP) were obtained before and 48 h following the infusion. Seven (58.3%) patients in the ROSU+ group and 13 (81.3%) in the ROSU- group experienced APR (P = not significant). No difference was found in fever and VAS measurements. CRP and granulocytes increased significantly in both groups; WBC count increased, while lymphocytes and eosinophils decreased significantly only in the ROSU- group. In a post hoc analysis of only patients with an APR, all laboratory parameters exhibited a similar significant change solely within the ROSU- group. In conclusion, our data suggest that a short course of ROS at this dose cannot prevent the ZOL-induced APR among osteoporotic women. Milder changes in acute-phase laboratory parameters in ROSU+ patients suggest that studies with higher doses may be warranted.

Objective: Parathyroid hormone increases the differentiation of osteoblast precursors through canonical wingless (Wnt) signalling, resulting in an osteoanabolic effect. We aimed to evaluate serum levels of the Wnt-inhibitor Dickkopf-1 (Dkk-1) in postmenopausal women with established osteoporosis and their changes with teriparatide (TPTD - human recombinant PTH 1-34)., Design and Patients: A total of 31 postmenopausal Caucasian women with established osteoporosis (mean age 66.3 +/- 1.4 years) received daily injections of 20 microg TPTD for 18 months. Follow-up was continued for another 6 months after treatment discontinuation (total duration of treatment 24 months)., Measurements: Serum samples for total calcium (Ca), intact PTH (iPTH), bone-specific alkaline phosphatase, C-terminal cross-linking telopeptide of type 1 collagen (CTx) and Dkk-1 were obtained at baseline, and at 6, 18 and 24 months after TPTD initiation. Lumbar spine bone mineral density (BMD) was measured before and after 18 months of TPTD treatment. A total of 16 age- and gender-matched healthy controls were also analysed at baseline., Results: Serum Dkk-1 levels at baseline were significantly higher in osteoporotic women compared with that in controls (P < 0.002). Dkk-1 increased significantly during TPTD administration (P < 0.044) and decreased to baseline 6 months after TPTD discontinuation. Dkk-1 change was positively correlated to Ca (r = 0.530, P = 0.004) and negatively correlated to iPTH change (r = -0.398, P = 0.040). There was no correlation between Dkk-1 and BMD changes., Conclusions: Our data suggest that Dkk-1 levels are increased in women with postmenopausal osteoporosis. TPTD therapy results in further increase of Dkk-1 that may be compensative to TPTD-induced enhanced Wnt signalling.

Intermittent exogenous parathyroid hormone (PTH) is a potent osteoanabolic agent used for the treatment of severe osteoporosis. Two molecules of recombinant PTH are commercially available: the full-length PTH (PTH 1-84) and teriparatide (PTH 1-34). We present the first report of PTH-induced mild, asymptomatic, normochromic normocytic anemia in a postmenopausal woman treated sequentially with PTH 1-84 and PTH 1-34. Anemia was more pronounced with PTH 1-84 compared to PTH 1-34 and was reversed with each regimen discontinuation. We suggest monitoring of hematocrit and hemoglobin in PTH-treated patients, especially when PTH 1-84 is used.

Receptor activator of nuclear factor-kappaB ligand (RANKL) is a cytokine essential for osteoclast differentiation, activation, and survival. Denosumab, a human monoclonal antibody against RANKL, constitutes a promising antiresorptive agent for osteoporosis. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and other trial registries through January 2009. We selected randomized controlled trials (RCTs) of denosumab in women with low bone mass that described the changes on bone markers and bone mineral density (BMD) as well as the adverse events including fracture risk. We analyzed data from nine RCTs involving 10 329 participants. Although denosumab universally decreased bone markers and increased lumbar and hip BMD, the efficacy evaluation based on percentage (%) mean change from the baseline was not possible due to missing data. Denosumab was not associated with a significant reduction in fracture risk [OR (95% CI) 0.74 (0.33 to 1.64), p=0.45]. Increased risk of serious adverse events [OR (95% CI) 1.83 (1.10 to 3.04), p=0.02] and serious infections [OR (95% CI) 4.45 (1.15 to 17.14), p=0.03] were evident. In conclusion, although effective as an antiresorptive agent, denosumab has not yet proved its efficacy on fracture risk reduction while increased infection risk questions its safety., (Georg Thieme Verlag KG Stuttgart.New York.)

Unlabelled: Objective To evaluate the effect of strontium ranelate (SR) on bone turnover markers in women with established osteoporosis previously treated with teriparatide (TPTD--recombinant human PTH 1-34). DESIGN PATIENTS: Twenty-two postmenopausal Caucasian women (aged 65.7 +/- 1.7 years) with established osteoporosis previously treated with TPTD 20 microg daily for 18 months were randomly assigned to receive either SR (SR group, n = 11) or calcium and vitamin D (control group, n = 11)., Measurements: Blood samples for serum N-terminal propeptide of type 1 collagen (P1NP), C-terminal telopeptide of type 1 collagen (CTx) and total alkaline phosphatase (ALP) were obtained from all women before (pre-TPTD) and after (post-TPTD) TPTD administration, as well as 6 months after SR or calcium/vitamin D administration (post-SR/Ca)., Results: Serum P1NP, CTx and total ALP increased significantly after TPTD treatment and decreased at the end of the study in both SR and control groups, with no difference between them., Conclusions: SR following TPTD administration acts predominantly as an antiresorptive agent with no evidence of additional osteoanabolic action. In this setting, SR is not more effective than Ca/vitamin D as far as bone turnover markers are concerned.

Introduction: Teriparatide (recombinant human PTH 1-34/TPTD) is an osteoanabolic agent available for osteoporosis treatment. The aim of this prospective trial was to evaluate the acute and chronic effects of TPTD in endogenous intact PTH (iPTH) levels in postmenopausal women with established osteoporosis., Materials and Methods: Thirty-six postmenopausal Caucasian women (age 66.6 1.4 years) with established osteoporosis received TPTD 20 mug once daily for eighteen months. Follow-up was continued for another six months after treatment discontinuation for a total of 24 months. Serum calcium, phosphate, total alkaline phosphatase (ALP) and iPTH were obtained from all women before and one hour, one day, as well as one, six, twelve, 18 and 24 months after treatment initiation. Lumbar spine bone mineral density was measured before, as well as twelve and eighteen months after treatment initiation., Results: iPTH levels decreased from the first hour of treatment, remained suppressed as long as TPTD was administered and increased after treatment discontinuation (p<0.001). Total ALP followed an opposite pattern. Serum calcium remained within normal range., Conclusions: iPTH levels are suppressed rapidly and persistently during TPTD administration whereas they return to baseline after treatment discontinuation; therefore, they can serve as an index of patient's compliance to treatment.

Aims: We aimed to compare the effect of risedronate (RIS) and teriparatide (TPTD) (recombinant human parathyroid hormone 1-34) on bone turnover markers in women with postmenopausal osteoporosis., Methods: Forty-four Caucasian women (age 65.1 +/- 1.6 years) with postmenopausal osteoporosis were randomly assigned to receive either RIS 35 mg once weekly (n = 22) or TPTD 20 microg once daily (n = 22) for 12 months. Serum N-terminal propeptide of type 1 collagen (P1NP), C-terminal telopeptide of type 1 collagen (CTx), total alkaline phosphatase (ALP) and intact parathyroid hormone (iPTH) were obtained from all women before, 3 and 6 months after treatment initiation. Lumbar spine bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry before and 12 months after treatment initiation., Results: P1NP, CTx and total ALP levels decreased in RIS group (p < 0.001) and increased in TPTD group (p < 0.001) throughout the treatment. iPTH increased significantly in RIS group (p < 0.05) and decreased in TPTD group (p < 0.001). Finally, lumbar spine BMD increased significantly in both RIS (p = 0.003) and TPTD groups (p < 0.001) without significant differences between them., Conclusions: Our data suggest that both serum P1NP and CTx are reliable markers of RIS and TPTD action in women with postmenopausal osteoporosis. In a similar way, serum total ALP can be used as an alternative marker for monitoring both RIS and TPTD action, while iPTH can be used only for TPTD-treated women. The increase in P1NP and CTx after 3 months of treatment with RIS or TPTD can predict the increase in BMD after 12 months of treatment.

Risedronate and teriparatide have opposite actions on the osteoblast-osteoclast dipole and are expected to influence the RANK/RANKL/osteoprotegerin (OPG) system. We aimed to evaluate changes in serum OPG and RANKL after risedronate or teriparatide administration in postmenopausal osteoporotic women. Seventy-four postmenopausal Caucasian women (age 64.1+/-1.0 years) were studied. Women with osteopenia served as controls (group 1, n=30). Women with osteoporosis were randomly assigned to either risedronate 35 mg once weekly (group 2, n=21) or teriparatide 20 microg once daily (group 3, n=23) for six months. Blood samples for serum RANKL, OPG, N-terminal propeptide of type 1 collagen (P1NP), and C-terminal telopeptide of type 1 collagen (CTx) were obtained before treatment and three and six months after treatment. P1NP and CTx levels remained unchanged in group 1, decreased in group 2 (p<0.001), and increased in group 3 women (p<0.001) throughout the treatment. OPG levels remained unchanged while RANKL decreased gradually in all groups (p<0.001). There was no correlation between OPG or RANKL and P1NP or CTx. Our data suggest that neither antiresorptive nor osteoanabolic therapy causes specific alterations of serum OPG/RANKL levels; therefore, these cytokines cannot substitute for the established markers of bone turnover in the monitoring of response to osteoporosis treatment.

Objective: The mechanisms regulating the anabolic response of the skeleton to intermittent exogenous parathyroid hormone (PTH) administration are not fully elucidated. The aim of this prospective study was to evaluate the acute effect (up to 1 month) of teriparatide (TPTD; human recombinant PTH 1-34) on serum levels of osteoprotegerin (OPG) and receptor activator for nuclear factor-kappaB ligand (RANKL) in women with established osteoporosis., Design: Twenty-three postmenopausal Caucasian women with established osteoporosis (mean age 66.7+/-1.6 years) received daily injections of 20 microg TPTD for 12 months., Methods: Serum samples for total calcium (Ca), phosphate, alkaline phosphatase, N-terminal propeptide of type I collagen, intact PTH (iPTH), OPG, and RANKL were obtained at baseline, 1 h, 1 day, and 1 month after initiation of therapy. Lumbar spine bone mineral density (BMD) was measured before and 12 months after TPTD treatment., Results: Serum total Ca increased and iPTH gradually decreased with TPTD treatment. Serum OPG levels remained unchanged, while RANKL increased gradually during the study (P<0.001). There was no correlation between OPG or RANKL and BMD changes or iPTH levels., Conclusions: TPTD therapy in women with postmenopausal osteoporosis results in acute increase in serum RANKL levels but does not affect serum OPG. These changes may reflect an increase in the number of active osteoblasts with therapy and might be responsible for the acceleration of bone turnover rate that characterizes TPTD.

Objective: Bisphosphonates are potent antiresorptive agents used for a spectrum of metabolic bone diseases. The aim of this study was to compare the adverse effects (AEs) of alendronate, etidronate and risedronate prescribed in a non-selected population, attending a single institution on an outpatient basis., Design: 849 patients receiving either alendronate (n=710), etidronate (n=181) or risedronate (n=130) were studied for a period of 1916 person-years., Results: AEs were reported by 25.2% [21% gastrointestinal (GI) system-related], 11.1% (9.9%) and 20.8% (15.4%) of patients on alendronate/etidronate/risedronate, respectively, resulting in permanent discontinuation in 21.0%, 7.7% and 13.8%, respectively. The odds ratio (95% Ci) for AEs in the case of a history of gi disease was 2.4 (1.4-3.8), 2.1 (0.8-5.1) and 2.5 (0.9-6.6), respectively. The majority of AEs were of a mild nature and usually occurred within six months of therapy initiation. The odds ratio for AEs given the concurrent use of NSAIDS was 2.0 (1.4-3.0), 0.8 (0.3-2.4) and 2.2 (0.8-5.9), respectively., Conclusions: Etidronate appears to have a better Ae profile. Bisphosphonate AEs are fairly mild, affect the gi system, occur most frequently in the presence of gi disease or concurrent use of NSAIDS and tend to be of the same type in the event of administration of a different bisphosphonate.