Introduction

The development of models to forecast fracture results has been discussed in several meetings and workshops, e.g. at the 2015 Food and Drug Administration Scientific Workshop and Osteoporosis Drug Development. The relations between variation in bone mineral density and fracture decrease was highly discussed on the agenda. Investigation of clinical studies with strontium ranelate reported no relationship between lumbar bone mineral density variation and the frequency of vertebral fractures and nonvertebral fractures1.

It was also reported that when interpreting the association between the increase in bone mineral density with vertebral fractures and nonvertebral, risk decrease by strontium ranelate treatment. It is essential to think through what part of the variations in bone mineral density by strontium ranelate treatment was caused by the higher atomic number of strontium (Z = 38) than the atomic number of calcium (Z = 20)2. The Food and Drug Administration and European Medicines Agency asked for evidence of fracture decrease efficiency in osteoporosis drug development and have uncertainties about the use of bone mineral density alone for fracture in randomized clinical trials3, 4. When bone mineral density is measured by dual-energy X-ray absorptiometry, strontium atoms in the bone reduce in X-rays more than calcium, causing over the assessment of the bone mineral density5. However, a larger increase in lumbar spine bone mineral density by alendronate treatments revealed a significant association with a lower risk of vertebral fracture6. A systematic review examined the association between the relative risks of vertebral fractures and nonvertebral fractures and intensifies the bone mineral density since a larger increase in bone mineral density is inclined to have greater anti-fracture effectiveness7. In these studies, however, the effects of other factors on the relationship were not measured. The changes in the ratio of subjects with predominant fracture between studies were masked in these studies.

A former meta-analysis of 11 cohort studies, in which osteoporotic fracture history and follow-up of fracture for individual subjects were performed, showed an association between past fractures and successive fractures8. The diagnosis guidelines for osteoporosis9 as well as the inclusion criteria for randomized clinical trials of osteoporosis drugs describe predominant osteoporotic fracture, including vertebral fractures and nonvertebral fractures, as a significant diagnostic criterion of osteoporosis. Previously, a study examined the relationship between the frequency of vertebral fractures and nonvertebral fractures in the placebo group and numerous demographic factors at baseline10.

Outcomes of this study showed that the proportion of subjects with predominant vertebral fractures and nonvertebral fractures had anassociation with the frequency of fracture, but the baseline bone mineral density T-score did not demonstrate a significant relationship with the frequency of vertebral fractures and nonvertebral fractures10. These outcomes showed that baseline bone mineral density T-scores do not forecast the frequency of vertebral fractures and nonvertebral fractures in the 3-year study period and recommend the need to assess the relationship between change in lumbar spine bone mineral density and the frequency of vertebral fractures and nonvertebral fractures.

Previous studies of osteoporosis drugs and a systematic review reported that a larger increase in bone mineral density tended to have greater anti-fracture efficacy6, 7. Although the change in lumbar spine bone mineral density showed a significant correlation with the incidence of new vertebral fractures and nonvertebral fractures, regardless of the adjustment with the proportion, bone mineral density showed a significant correlation with the incidence of new vertebral fractures and nonvertebral fractures in both the higher and lower tertile group without the adjustment with the proportion of subjects with prevalent vertebral fractures and nonvertebral fractures11-30. Therefore, we suggest that the main factor leading to a model fitting in the meta-analysis study was the difference in the risk of new vertebral fractures and nonvertebral fractures among the study populations with different prevalence of vertebral fractures and nonvertebral fractures.

This indicates that the correlation between the change in bone mineral density and the incidence of new vertebral fractures and nonvertebral fractures is different between the study populations with a high and low prevalence of vertebral fractures and nonvertebral fractures; the higher prevalence of vertebral fractures and nonvertebral fractures the study group has, the greater the effect of the increase in lumbar spine bone mineral density on the prevention of new vertebral fractures and nonvertebral fractures observed. The degree of prevalence of vertebral fractures and nonvertebral fractures in the population should be considered when the association between change in lumbar spine bone mineral density and incidence of vertebral fractures and nonvertebral fractures is examined. From all this, it is obvious that studies have shown that the change in lumbar spine bone mineral density with different osteoporosis drugs had a beneficial effect on the frequency of new vertebral fractures and nonvertebral fractures in postmenopausal females, but their results were conflicting11-30.

The present meta-analysis study aimed to examine the relationship between the change in lumbar spine bone mineral density and the frequency of new vertebral fractures and nonvertebral fractures in postmenopausal females.

Methods

The study performed here followed the meta-analysis of studies in the epidemiology statement31, which was conducted following an established protocol as shown in Table S1 for PRISMA checklist as a basis for reporting systematic reviews objectives and evaluating interventions.

Study Selection

Studies included were retrospective or randomized clinical trials evaluating the relationship between the change in lumbar spine bone mineral density and the frequency of new vertebral fractures and nonvertebral fractures in postmenopausal females.

Only human studies in the English language were considered. Inclusion was not limited by study size or publication type. Publications excluded were review articles and commentary and studies that did not deliver a measure of an association. The articles were integrated into the meta-analysis when the following inclusion criteria were met: (i) the study was a randomized controlled trial; (ii) the target population was postmenopausal females; (iii) the intervention program was based on osteoporosis drugs' effect on change in lumbar spine bone mineral density; (iv) the study included a comparison between osteoporosis drugs and placebo (Fig. 1).

Schematic diagram of the study operation

Identification

A protocol of search strategies was prepared according to the PICOS principle32, and we defined it as follows: P (population): postmenopause females; I (intervention/exposure): osteoporosis drugs effect on change in lumbar spine bone mineral density; C (comparison): osteoporosis drugs compared to placebo; O (outcome): frequency of new vertebral fractures and nonvertebral fractures in postmenopausal females; and S (study design): no restriction33.

First, we conducted a systematic search of OVID, Embase, Cochrane Library, PubMed, and Google scholar till May 2020, using a blend of keywords and similar words for an osteoporosis drug, bone mineral density, lumbar spine, vertebral fracture, and nonvertebral fracture as shown in Table 1. All identified studies were pooled in an EndNote file, duplicates were omitted, and the title and abstracts were reviewed to exclude studies that did not report a relationship between the change in lumbar spine bone mineral density and the frequency of new vertebral fractures and nonvertebral fractures in postmenopausal females.

TABLE 1. Search strategy for each database Database Search strategy Pubmed

#1 “osteoporosis drug”[MeSH Terms] OR “Bone mineral density”[All Fields] OR “lumbar spine”[All Fields] OR “Vertebral fracture”[All Fields]

#2 “nonvertebral fracture”[MeSH Terms] OR “osteoporosis drug”[All Fields] OR “acceptability”[All Fields] OR “Live birth”[All Fields]

#3 #1 AND #2

Embase

‘osteoporosis drug’/exp. OR ‘Bone mineral density’/exp. OR ‘lumbar spine’/exp. OR Vertebral fracture

#2 ‘nonvertebral fracture’/exp. OR ‘ICBG’/exp. OR ‘acceptability’/exp. OR Live birth

#3 #1 AND #2

Cochrane library

(osteoporosis drug):ti,ab,kw (Bone mineral density):ti,ab,kw OR (lumbar spine): ti,ab,kw (Word variations have been searched)

#2 (Vertebral fracture):ti,ab,kw OR (nonvertebral fracture):ti,ab,kw OR (acceptability):ti,ab,kw OR (Live birth): ti,ab,kw (Word variations have been searched)

#3 #1 AND #2

Screening

Data were abridged on the following study-related and subject-related characteristics onto a standardized form: last name of the primary author, period of study, year of publication, country, region of the studies, and study design; population type, the total number of fractures, demographic data and clinical and treatment characteristics; postoperative risks, qualitative and quantitative method of evaluation, information source, and outcome evaluation; and statistical analysis34. When there were different data from one study, we extracted them independently.

The risk of bias in these studies was assessed as follows. Individual studies were evaluated using the quality in prognosis studies tool, which evaluates validity and bias in studies of prognostic factors across six domains: participation, attrition, prognostic factor measurement, confounding measurement and account, outcome measurement and analysis, and reporting35. Any inconsistencies were addressed by a re-evaluation of the original article.

Eligibility

The main outcome focused on the relationship between the change in lumbar spine bone mineral density and the frequency of new vertebral fractures and nonvertebral fractures in postmenopausal females.

Inclusion

Sensitivity analyses were limited only to studies reporting the relationship between the change in lumbar spine bone mineral density and the frequency of new vertebral fractures and nonvertebral fractures in postmenopausal females with different osteoporosis drugs compared to placebo. For subcategory and sensitivity analysis, we used comparisons between different osteoporosis drugs compared to placebo.

Statistical Analysis

The dichotomous method with a random-effect model or fixed-effect was used to calculate OR and 95% CI. The I2 index was calculated; the I2 index is between 0% and 100%. Values of about 0%, 25%, 50%, and 75% indicate no, low, moderate, and high heterogeneity, respectively36. When I2 was higher than 50%, we chose the random effect model; when it was lower than 50%, we used the fixed-effect model. A subcategory analysis was completed by stratifying the original evaluation per outcome categories as described before. In this analysis, a P-value for differences between subcategories of <0.05 was considered statistically significant. Publication bias was evaluated quantitatively using the Egger regression test (publication bias considered present if P ≥ 0.05), and qualitatively, by visual examination of funnel plots of the logarithm of ORs vs their standard errors (SE)32. All P-values were two-tailed. All calculations and graphs were performed using reviewer manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).

Results Search

A total of 1801 unique studies were identified, of which 20 studies fulfilled the inclusion criteria and were included in the study11-30. Details of included studies are shown in Table 2.

TABLE 2. Characteristics of the selected studies for the meta-analysis Study Year Treatment used Country Total Treatment Placebo Harris, 199316 1993 Cyclic etidronate USA 380 196 184 Liberman, 199528 1995 Alendronate USA, Belgium, and Israel 881 526 355 Black, 199615 1996 Alendronate USA 2027 1022 1005 Ettinger, 199929 1999 Raloxifene North and South America, and Europe 7038 4746 2292 Harris, 199919 1999 Risedronate USA 1374 696 678 Chesnut III, 200020 2000 Spray salmon calcitonin USA 1108 838 270 Reginster, 200014 2000 Risedronate Australia, and Europe 1686 1006 680 Alexandersen, 200130 2001 Iprifravone Europe 473 234 239 Chesnut III, 200418 2004 Oral ibandronate USA, and Europe 2929 1954 975 Recker, 200417 2004 Ibandronate USA, and Europe 2859 1910 949 Meunier, 200413 2004 Strontium ranelate Australia, and Europe 1442 719 723 Black, 200721 2007 zoledronic acid USA, New Zealand, and Europe 5675 2822 2853 Cummings, 200825 2008 Tibolone USA, and Europe 4506 2249 2257 Silverman, 200822 2008 Raloxifene or Bazedoxifene USA, South Africa, Croatia, Denmark, and Argentina 4991 3735 1256 Cummings, 200926 2009 Denosumab USA, and Europe 7393 3702 3691 Cummings, 201023 2010 Lafosoxifene USA, and Europe 8226 5482 2744 Cummings, 201124 2011 Arzoxifene North and South America, and Europe 9354 4676 4678 Jacques, 201212 2012 Zoledronic Acid USA 5907 2931 2976 Henriksen, 201627 2016 Oral salmon calcitonin Brazil, and Europe 4189 2064 2125 Okubo, 202011 2020 Denosumab Japan 952 472 480 Total 73390 41980 31410 Note: Bold values shown total of the above values. Baseline Characteristics

The 20 studies included 73,390 postmenopausal females; of them, a total of 41,980 were treated with osteoporosis drugs, and 31,410 were treated with placebo. All studies were for the determination of the relationship between the change in lumbar spine bone mineral density and the frequency of new vertebral fractures and nonvertebral fractures in postmenopausal females.

Study size ranged from 380 to 9345 subjects at the start of the study with 196 to 5482 treated with osteoporosis drugs. Twenty studies reported data stratified comparison related to vertebral fractures, and 14 studies related to nonvertebral fractures in postmenopausal females.

The extent of the incidence of vertebral fractures and nonvertebral fractures in postmenopausal females was studied. Treatment with osteoporosis drug groups had a significantly lower frequency of new vertebral fractures and nonvertebral fractures compared to placebo in postmenopausal females and this was in all populations studied.

Osteoporosis Drugs vs Placebo

Treatment with osteoporosis drugs had significantly lower frequency of new vertebral fractures (OR, 0.53; 95% CI, 0.45–0.63, P  < 0.001) with high heterogeneity (I2 = 84%); and lower nonvertebral fractures (OR, 0.82; 95% CI, 0.78–0.87, P  < 0.001) with no (I2 = 1%) compared to placebo in postmenopausal females as shown in Figs 2 and 3.

Forest plot of the frequency of new vertebral fractures in treatment with the osteoporosis drugs group compared to the placebo group in postmenopausal females

Forest plot of the frequency of new nonvertebral fractures in treatment with the osteoporosis drugs group compared to the placebo group in postmenopausal females

A stratified analysis of studies that did and did not adjust for the effect of osteoporotic fracture history, gender, and ethnicity on the results was not performed because no studies reported or adjusted for these factors.

Quality Assessment

Based on the visual inspection of the funnel plot (Figs S1 and S2, as a visual aid for detecting bias or systematic heterogeneity) as well as on quantitative measurement using the Egger regression test, there was no evidence of publication bias (P  = 0.87) as shown in Fig. 4.

Risk of bias summary

Discussion Osteoporosis Drugs vs Placebo

The relationship between the change in lumbar spine bone mineral density and the frequency of new vertebral fractures and nonvertebral fractures in postmenopausal females was variable in the selected studies. In this meta-analysis study, based on 20 studies with 73,390 postmenopausal females, a total of 41,980 were treated with osteoporosis drugs and 31,410 with placebo. Treatment with osteoporosis drug groups had a significantly lower frequency of new vertebral fractures and nonvertebral fractures compared to placebo in postmenopausal females. This effect was observed primarily in all subjects11-30. This finding suggests that the treatment with osteoporosis drugs had better results in a lower frequency of new vertebral fractures and nonvertebral fractures in postmenopausal females compared to placebo.

The outcomes of this study showed the need for further research on the osteoporosis drugs as a single preventer of the new vertebral fractures and nonvertebral fractures in postmenopausal females to consolidate the finding11-30, since the use of osteoporosis drugs in postmenopausal females are controversial. Many studies have been carried out comparing osteoporosis drugs to placebo in postmenopausal females11-30.

Previous Clinical Trial Studies

Previous clinical trial studies of osteoporosis drugs showed that larger intensification in bone mineral density is inclined to have better anti-fracture efficiency6, 7. We recommend that the intensification in lumbar spine bone mineral density relates to the inhibition of new fractures under situations where the osteoporosis drug does not disturb the dual-energy X-ray absorptiometry quantity. Though, the change in lumbar spine bone mineral density in osteoporosis drug studies presented a significant relationship with the frequency of new fractures irrespective of the modification in the proportion of subjects with predominant vertebral and nonvertebral fracture11-30. This outcome showed that the model with the modification more accurately forecasts the frequency of new vertebral fractures and nonvertebral fractures than the model without the modification. Numerous factors could lead to this outcome. First, in a meta-analysis of cohort studies and the earlier meta-regression analysis in the placebo group in clinical trials, the frequency of vertebral fractures and nonvertebral fractures has a significant association with the frequency of successive vertebral fractures and nonvertebral fractures8, 10, 37. These outcomes show that the higher the frequency of vertebral fractures and nonvertebral fractures, the higher the frequency of new vertebral fractures and nonvertebral fractures witnessed. So, alterations in the frequency of vertebral fractures and nonvertebral fractures between any study populations ought to be considered when comparing the fracture inhibition effect of a certain drug. Second, the vertebral fracture frequency itself affects bone mineral density quantity. L1 is one of the places in which fractures most often happen38; one or two fractures in the lumbar spine increase bone mineral density39. The International Society of Clinical Densitometry has suggested that anatomically abnormal vertebrae should be excluded from analysis if they are abnormal and non-quantifiable within the resolution of the system, or if there is more than a 1.0 T-score variation among the vertebra studied and the adjacent vertebrae40. It can be deduced that vertebral fractures and nonvertebral fractures disturb the measurement of lumbar spine bone mineral density, and the frequency of vertebral fractures and nonvertebral fractures decreases the precision of fracture risk forecast by bone mineral density. So, we recommend that the chief factor leading to the outcome of model fitting was the variation in the risk of new vertebral fractures and nonvertebral fractures between the study populations with a different frequency of vertebral fractures and nonvertebral fractures. The current outcomes of the subgroup analysis showed a significant interaction between the proportion of subjects with predominant vertebral fractures and nonvertebral fractures and the percentage variation in lumbar spine bone mineral density from baseline at 3 years41-44. The degree of frequency of vertebral fractures and nonvertebral fractures in the population must be considered when the correlation between variation in lumbar spine bone mineral density and frequency of vertebral fractures and nonvertebral fractures is observed.

Recommendations

From the present study, Treatment with osteoporosis drugs had a significantly lower frequency of new vertebral fractures and nonvertebral fractures compared to placebo in postmenopausal females11-30. These outcomes have vital benefits in postmenopausal females11-30.

This relationship forces us to recommend osteoporosis drugs in postmenopausal females to avoid any possible new fractures. A cost-effective study is recommended for better results.

Our meta-analysis study could not answer whether the effect of osteoporotic fracture history, gender, and ethnicity are associated with different results since most of the studies did not adjust for these factors. Larger prospective studies are recommended to confirm these findings and adjust for the effect of osteoporotic fracture history, gender, and ethnicity.

Limitations

First, the analysis was not completed at the patient level but was instead based on summary data. Second, data from randomized clinical trials were used in this study. The features of subjects in clinical trials of a new treatment may have influenced the generalizability of this study outcome. Third, numerous latest clinical trials for osteoporosis drugs such as romosozumab and odanacatib, which showed radical intensifications in bone mineral density, were not included in this study due to their short study period or hidden study outcomes. Further studies are needed to show why these big variations in bone mineral density in a short study period occurred.

Conclusions

Treatment with osteoporosis drugs had a significantly lower frequency of new vertebral fractures and nonvertebral fractures compared to placebo in postmenopausal females. This relationship forces us to recommend osteoporosis drugs in postmenopausal females to avoid any possible new fractures. However, the degree of frequency of vertebral fractures and nonvertebral fractures in the population should be considered when the association between variation in lumbar spine bone mineral density and frequency of vertebral fractures and nonvertebral fractures is inspected. Also, cost-effective studies are needed.

Acknowledgments

This project was supported by Jiangsu University Clinical Medicine Science and Technology Development Fund(No:JLY20180078) and Jiangsu Health International Exchange Program and Key medical talents project of Wuxi Commission of Health (ZDRC018). All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Declarations Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

The authors declare that they have no competing interests.

Authors' Contributions

Conception and design: LC and MA. Administrative support: All authors. Provision of study materials or subjects: All authors. Collection and assembly of data: LC, JC, LZ. Data analysis and interpretation: All authors. Manuscript writing: All authors. Final approval of manuscript: All authors. All authors have read and approved the manuscript.

IRB Approval

Not required for this study.