Anabolic and antiresorptive therapy for osteoporosis: combination and sequential approaches.The effects of anabolic medications teriparatide [TPTD] and ansbolic hormone [PTH] differ in antiresorptive anabolic who have received recent treatment with potent antiresorptives. Effect of treatment sequence on spine BMD outcome is minor, with modest quantitative differences. This transient hip BMD loss is more prominent when the antiresorptive is denosumab; in this setting, antiresorptive anabolic BMD remains below baseline for almost a full 24 antiresorptive anabolic. Furthermore, hip strength improved with the addition of TPTD to stanozolol vende em farmacia alendronate, whereas it was neutral after switching from alendronate to TPTD, antirdsorptive due to the effect on cortical bone. Bone biopsy studies indicate that TPTD stimulates bone formation in patients who have not been treated previously as well as in patients on prior and ongoing antiresorptive anabolic. When possible, we suggest anabolic therapy first, followed by potent antiresorptive therapy. The common practice of switching to TPTD only after patients have an inadequate response to antiresorptives intercurrent fracture or inadequate BMD effect is not the optimal utilization of anabolic treatment.
New insights into treatment of osteoporosis in postmenopausal women | RMD Open
Colleague's E-mail is Invalid. Your message has been successfully sent to your colleague. According to the mechanisms of action, combination therapy of anabolic and antiresorptive agents may produce more effect for the treatment of osteoporosis. However, the combination therapy of anabolic agents and bisphosphonates reports no benefit and even reduced the anabolic effects of anabolic agents.
This study aims to assess the effect of combination therapy of anabolic and nonbisphosphonates antiresorptive agents in adults with osteoporosis.
Medline, EMBASE, and Cochrane Library were searched from January 1, to November 1, for randomized controlled trials RCTs of adults with osteoporosis treated in combination therapy of anabolic and nonbisphosphonates antiresorptive agents compared with monotherapy of either agent alone.
The primary outcome was the incidence of fractures. The secondary outcomes were the bone mineral density BMD changes at lumbar spine and total hip. The meta-analysis was performed using a random-effects model. A total of 10 trials with a total of patients were included. The pooled results showed that the combination therapy demonstrated a significant advantage over a monotherapy in the BMD improvement at the lumbar spine SMD 1. Low-to-moderate-quality evidence shows that the combination therapy of anabolic and nonbisphosphonates antiresorptive agents is superior to monotherapy in improving the BMD and reducing the fracture risk.
However, further high methodological quality studies are needed to determine the antifracture efficacy, cost-effectiveness and safety of this strategy of combination therapy. YW conceived and designed the experiments and reviewed the draft. SL and LW performed the experiments, analyzed the data, wrote the paper, prepared the figures and tables and reviewed the draft.
YW, YJ and JL contributed to the design of the search strategy, prepared the figures and tables and reviewed the draft. Supplemental digital content is available for this article. The work cannot be changed in any way or used commercially without permission from the journal. Osteoporosis is a common skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, causing an increase in bone fragility and susceptibility to fracture.
To date, a range of pharmacological interventions is available for the treatment of osteoporosis. Depending on their mechanism of action, antiosteoporosis medications can be classified into either antiresorptive agents or anabolic agents. Antiresorptive agents include bisphosphonates, hormone replacement therapy HRT , raloxifene, denosumab, and calcitonin. Owing to improve the treatment efficacy, combination strategy by using antiresorptive and anabolic agents simultaneously was proposed.
Since bisphosphonates are the most commonly used antiresorptive agents for the treatment of osteoporosis , the combination therapy of anabolic agents and bisphosphonates was initially thought to be a promising approach.
Unfortunately, this combination strategy reported no benefit and even reduced the anabolic effects of anabolic agents. Thus, the objective of this meta-analysis of randomized controlled trials RCTs is to determine whether the combination therapy of anabolic and nonbisphosphonates antiresorptive agents produces more effects on BMD and reduce the incidence of fractures than monotherapy in adults with osteoporosis. This study was not a human or animal experiment, so no ethical approval was required.
Moreover, reference lists from retrieved trials, reports, conference abstracts, and reviews were manually scanned to further identify potentially eligible trials. We used the following inclusion criteria. Participants were adults with osteoporosis. Diagnosis criterion of osteoporosis was as follow: The intervention was a combination therapy of anabolic agents and nonbisphosphonates antiresorptive agents. The comparator was a monotherapy with either anabolic agents or nonbisphosphonates agents alone or monotherapy plus placebo.
The outcomes included the incidence of fractures and the BMD variation. All relevant RCTs written in any language were included. Discrepancies were resolved through discussion with a third reviewer YSW. Extracted data included the following major categories: For continuous outcomes, the sample size, mean, and SD were extracted for each experimental group and control group. For dichotomous outcomes, we extracted the original data regarding the events and the total number in both the experimental group and the control group.
We attempted to contact study authors for additional information when necessary. The primary outcome is the incidence of fractures confirmed by x-ray radiography. Both vertebral and nonvertebral fractures were included. Nonvertebral fractures were documented as wrist, humerus, clavicle, pelvis, vertebrae, hip, ankle, metatarsal, or other.
The secondary outcomes are BMD changes measured by dual-energy x-ray absorptiometry, DXA at the lumbar spine and the total hip. Bias was assessed across the following 7 domains: Each aspect could further be classified as a low, high or unclear risk. For the study design, we assessed random-sequence generation, allocation concealment, blinding of the participants and outcome reporting.
For each outcome, we assessed blinding of the outcome assessors and loss to follow-up. The meta-analysis was performed using a random-effects model, which provided more conservative estimated effects. When there was a significant heterogeneity, sensitivity analyses were conducted using sequential omission of a single study from the total studies to evaluate the influence of each study on the pooled effect estimates. To further explore possible sources of heterogeneity, preplanned subgroup analyses were performed based on the different mechanisms of antiosteoporosis medications anabolic agents versus nonbisphosphonates antiresorptive agents.
And meta-regression analyses were used to evaluate the relationship between the duration of therapy, the age, and the outcomes. A 2-sided P value of less than or equal to.
The quality of the evidence was assessed according to using the Grading of Recommendations Assessment, Development, and Evaluation GRADE guidelines, which uses the domains of risk of bias, inconsistency, indirectness, imprecision, and publication bias in in results.
A total of articles were obtained through electronic and hand searches. After duplicates were removed, the titles and abstracts of records were reviewed, records were excluded for not meeting the inclusion criteria, and thus the remaining 15 articles were retrieved, all written in English, for further assessment.
Five trials were excluded due to reports of repeated data [16—19] and nonosteoporotic patients. The main characteristics of the included trials are summarized in Table 1. These trials were published from to and involved totally patients, with the sample sizes ranging from 42 to The duration of treatment lasted from 6 to 36 months.
All patients received oral calcium and vitamin D supplements daily. Figure 2 summarizes the details of the risk of bias. Random sequence generation was reported in 5 trials [6,21—23,28] and was not described in the remaining trials.
Allocation concealment was adequately reported in 2 trials. However, whether or not the participants and investigators were blind has limited impact on the changes in BMD. Blinding of outcome assessment was adequately reported in all the 10 trials except for 2. There was a low risk of reporting bias, and other biases in all the included trials. Five trials [21—24,28] provided the available data about the incidence of fractures. Compared with monotherapy, the combination therapy could achieve a greater reduction of fracture incidence RR, 0.
Subgroup analyses showed that when compared with nonbisphosphonates agents alone, the combination therapy could reduce the risk of fractures RR, 0. However, the currently available evidence is insufficient to support the combination therapy is superior to monotherapy with anabolic agents for the prevention of fractures RR, 0. There was no evidence of publication bias in the overall pooled result, with Egger's test P value of. Ten trials [6,21—29] reported the BMD changes at the lumbar spine.
Sensitivity analyses were performed to examine the robustness of our analysis by omitting each study in turn, and the pooled SMD was significantly affected by the study of Cosman  SMD 0. Subgroup analyses showed that whether compared with anabolic agents SMD 0.
Ten trials [6,21—29] provided total hip BMD data and were included in the analysis. Subgroup analyses showed that compared with monotherapy with either anabolic agents SMD 0. There was an evidence of publication bias, with the Egger's test P value of. All the included trials were RCTs and had no serious inconsistency, indirectness, or imprecision.
Risk of bias existed in each outcome, and the most common causes of the decreased level of evidence were the unclear random sequence generation and the unclear allocation concealment. Reporting bias existed in the outcome of BMD changes at the total hip. Although the included RCTs were considered as high-quality evidence, the quality was lowered because of the above limitations.
The strength of inference was therefore limited and the available evidence of each outcome was moderate to low. Our meta-analysis comprehensively and systematically reviews the current available literature and provides low-to-moderate-quality evidence that the combination therapy of anabolic nonbisphosphonates antiresorptive agents is superior to monotherapy in improving the BMD at the lumbar spine and total hip.
This study also provides moderate-quality evidence that this combination therapy has an advantage than monotherapy in reducing the fracture incidence. Meanwhile, our meta-regression analyses suggested that the treatment duration had a significant relationship with the results, which might be the main reason for the significant heterogeneity. Among the included trials, the treatment duration lasted from 6 to 36 months.
It was suggested that owing to the subsequent resistance to anabolic agents suggested that to increase BMD, anabolic agents might best be used for periods of 6 to 12 months or less. In addition, it was suggested that the effect of combination therapy seemed to be affected by the potency of antiresorptive agents.
Although the diverse settings brought some heterogeneity, the heterogeneity has been well explained, and the diverse settings considerably improved the generalizability and usefulness of our meta-analysis.
Monotherapy was the current standard treatment for osteoporosis. Antiresorptive agents could reduce bone resorption, were the first line drugs. Anabolic agents could increase bone formation, were the second line drugs.
However, due to the coupling of bone resorption and formation, antiresorptive agents not only inhibit bone resorption but also inhibit bone formation, thereby mitigating the potential benefit of the antiresorptive effect, similarly, antiresorptive agents increase bone formation also increase bone resorption, which affecting the anabolic ability.
Based on our results, although current evidence does not yet support a change in clinical practice, combination therapy may be appropriate for certain patients with osteoporosis. Moreover, since anabolic agents were approved for a limited period 18—24 months , a sequential therapy was required due to the short duration.
According to current evidence, when using sequential therapy with monotherapy, for patients previously treated with anabolic agents alone, sequential therapy with an antiresorptive agent is recommended to maintain and further increase the BMD. This study also has limitations. Given these limitations, results of this meta-analysis should be interpreted cautiously.