Epidemiological burden of postmenopausal osteoporosis in France from 2010 to 2020: estimations from a disease model

Summary

This article estimates the present and future burden of postmenopausal osteoporosis in France in women aged 50?years and over.

Methods

We adapted an existing model developed for Sweden to France. For each year of the study from 1970 to 2020, the ??incident cohort?? (women experiencing a first osteoporotic fracture) was identified and run through a Markov model using annual cycles. Health states were based on the number of fractures (hip, vertebral, non-hip non-vertebral) and deaths. Transition probabilities reflected fracture site-specific risks of subsequent fractures and of death. Country-specific model inputs included population size and life tables from 1970 to 2020 and incidence of hip fracture.

Results

The model estimated that the number of postmenopausal osteoporotic women was expected to increase from 3.0 million to 3.4 million between 2010 and 2020 (+15.3?%). Assuming that the incidence of fracture by age group does not change over time, the model predicted that the overall number of osteoporotic fractures would increase from 204,234 fractures in 2010 to 241,261 in 2020 (+18.1?%), hip (20.3?%), vertebral (19.0?%) and non-hip non-vertebral fractures (17.0?%).

Conclusion

The aging of the population is expected to drive a marked increase in the prevalence of osteoporosis and in the number of osteoporotic fractures. These data may assist future planning for appropriate heath care provision.     

Postmenopausal osteoporosis treatment with antiresorptives: effects of discontinuation or long-term continuation on bone turnover and fracture risk--a perspective

Osteoporosis may be a lifelong condition. Robust data regarding the efficacy and safety of both long-term osteoporosis therapy and therapy discontinuation are therefore important. A paucity of clinical trial data regarding the long-term antifracture efficacy of osteoporosis therapies necessitates the use of surrogate endpoints in discussions surrounding long-term use and/or discontinuation. Long-term treatment (beyond 3-4 years) may produce further increases in bone mineral density (BMD) or BMD stability, depending on the specific treatment and the skeletal site. Bisphosphonates, when discontinued, are associated with a prolonged reduction in bone turnover markers (BTMs), with a very gradual increase to pretreatment levels within 3 to 60 months of treatment cessation, depending on the bisphosphonate used and the prior duration of therapy. In contrast, with nonbisphosphonate antiresorptive agents, such as estrogen and denosumab, BTMs rebound to above pretreatment values within months of discontinuation. The pattern of BTM change is generally mirrored by a more or less rapid decrease in BMD. Although the prolonged effect of some bisphosphonates on BTMs and BMD may contribute to residual benefit on bone strength, it may also raise safety concerns. Adequately powered postdiscontinuation fracture studies and conclusive evidence on maintenance or loss of fracture benefit is lacking for bisphosphonates. Similarly, the effects of rapid reversal of bone turnover upon discontinuation of denosumab on fracture risk remain unknown. Ideally, studies evaluating the effects of long-term treatment and treatment discontinuation should be designed to provide head-to-head "offset" data between bisphosphonates and nonbisphosphonate antiresorptive agents. In the absence of this, a clinical recommendation for physicians may be to periodically assess the benefits/risks of continuation versus discontinuation versus alternative management strategies.     

Differing risk profiles for individual fracture sites: Evidence from the global longitudinal study of osteoporosis in women (GLOW)

The purposes of this study were to examine fracture risk profiles at specific bone sites, and to understand why model discrimination using clinical risk factors is generally better in hip fracture models than in models that combine hip with other bones. Using 3-year data from the GLOW study (54,229 women with more than 4400 total fractures), we present Cox regression model results for 10 individual fracture sites, for both any and first-time fracture, among women aged ≥55 years. Advanced age is the strongest risk factor in hip (hazard ratio [HR] = 2.3 per 10-year increase), pelvis (HR = 1.8), upper leg (HR = 1.8), and clavicle (HR = 1.7) models. Age has a weaker association with wrist (HR = 1.1), rib (HR = 1.2), lower leg (not statistically significant), and ankle (HR = 0.81) fractures. Greater weight is associated with reduced risk for hip, pelvis, spine, and wrist, but higher risk for first lower leg and ankle fractures. Prior fracture of the same bone, although significant in nine of 10 models, is most strongly associated with spine (HR = 6.6) and rib (HR = 4.8) fractures. Past falls are important in all but spine models. Model c indices are ≥0.71 for hip, pelvis, upper leg, spine, clavicle, and rib, but ≤0.66 for upper arm/shoulder, lower leg, wrist, and ankle fractures. The c index for combining hip, spine, upper arm, and wrist (major fracture) is 0.67. First-time fracture models have c indices ranging from 0.59 for wrist to 0.78 for hip and pelvis. The c index for first-time major fracture is 0.63. In conclusion, substantial differences in risk profiles exist among the 10 bones considered. © 2012 American Society for Bone and Mineral Research.     

The effects of hormone replacement therapy on cortical bone in postmenopausal women. A histomorphometric study

Investigations of the actions of estrogen on the skeleton have mainly focused on cancellous bone and there are no reported histomorphometric studies of the effects of oestrogen on cortical bone in humans. The aim of this study was to investigate the effects of both conventional hormone replacement therapy (HRT) and high-dose oestradiol on cortical bone in postmenopausal women. Transiliac biopsies were obtained from nine postmenopausal women aged 54-71 yr before and after 2 yr (mean, 23.5 months) of conventional HRT and in seven postmenopausal women aged 52-67 yr after long-term, high-dose oestradiol implant therapy (at least 14 yr). Indices of bone turnover, remodeling, and cortical structure were assessed by image analysis. Cortical width was highest in the women treated with high-dose oestrogen therapy (2.29 +/- 0.78 mm; mean +/- SD) and lowest in untreated women (1.36 +/- 0.60 mm; P=0.014). The proportion of canals with an eroded surface was significantly lower in the high-dose oestrogen group than in women before or after conventional HRT (3.03 +/- 3.7% vs. 11.1 +/- 7.1% and 10.5 +/- 8.6%; P=0.017 and 0.05, respectively). Bone formation rate (microm2/microm/day) in untreated women was significantly higher than in the high-dose oestrogen group (0.121 +/- 0.072 vs. 0.066 +/- 0.045, respectively; P=0.05), values in women treated with conventional HRT being intermediate. Our results provide the first histomorphometric evidence in postmenopausal women of dose-dependent oestrogen-induced suppression of bone turnover in iliac crest cortical bone. There was also a trend toward higher wall width with increasing dose of oestrogen, consistent with the previously reported anabolic effect in cancellous bone.     

A Histomorphometric Study of Cortical Bone of the Iliac Crest in Patients Treated with Glucocorticoids

The effects of glucocorticoids on cancellous bone remodeling and structure are well documented but there are no reported histomorphometric studies in human cortical bone in glucocorticoid-treated patients. We have performed a histomorphometric analysis of iliac crest cortical bone in 14 patients treated with glucocorticoids, 9 females and 5 males, aged 18 to 48 years (34.1 ± 7 years) (mean ± standard deviation [SD]). The underlying disease was cystic fibrosis in 8 patients; asthma 3; and nephrotic syndrome; Crohn disease and inflammatory pseudotumor of the liver in one patient each. Results were compared with an age-matched control group of 10 premenopausal women and 4 men aged 22 to 38 years (30.1 ± 4.8 years) who were not, howerver matched for underlying disease. Cortical bone indices were assessed by image analysis. Cortical width and area were similar in the two groups. However, cortical porosity, Haversian canal number, and density were higher in patients treated with glucocorticoids compared with controls (8.4 ± 8.9% vs. 5.1 ± 3.9%; P = 0.03) (45.9 ± 23.2 vs. 31.9 ± 24.4; P =0.003) (13.7 ± 9.4 vs. 6.7 ± 3.3/mm²; P = 0.00005). Haversian canal area did not differ significantly between groups. The mean wall width of the osteons, bone formation rate (μm²/μm/day) and mineral apposition rate (μm/day) were lower in treated patients compared to controls (48.8 ± 7.1 μm vs. 59.8 ± 12.9 μm; P = 0.01) (0.056 ± 0.040 vs. 0.095 ± 0.058; P = 0.05) and (0.59 ± 0.12 vs. 0.75 ± 0.11; P = 0.002). The proportion of canals with an eroded surface was lower in the treated compared with the control group, although this difference was not statistically significant. These results demonstrate that cortical porosity is increased in patients treated with long-term glucocorticoid therapy, due mainly to an increase in the number rather than size of Haversian canals. This may be because of increased bone resorption during the early stages of glucocorticoid therapy, in combination with long-term impairment of bone formation. Effects of the underlying disease on bone remodeling may also contributed to these changes and could not be excluded in the present study; since control subjects were not matched in terms of disease status.     

Megakaryocytes modulate osteoblast synthesis of type-l collagen, osteoprotegerin, and RANKL

We have previously reported evidence that megakaryocytes may play a role in bone remodeling, possibly by interactions with cells at the bone surface. To investigate the direct effects of megakaryocytes on osteoblasts, maturing megakaryocytes (CD61 positive cells) were isolated and added to cultures of human osteoblasts. Osteoblasts alone and osteoblasts treated with CD61-negative (non-megakaryocytic) cells were used as control cultures. After 48 h in culture, megakaryocytes were removed and osteoblasts immunolocalized for type-1 collagen, osteoprotegerin (OPG), and RANKL expression. Similar cultures were used for RNA extraction with mRNA for Col 1A1, OPG, and RANKL in osteoblasts measured quantitatively by RT-PCR. Osteoblasts cultured alone showed high levels of expression of collagen with 74% (+/-7) of cells staining positively. When cultured with megakaryocytes, the number of positively staining cells remained similar but the intensity of expression was increased 1.54-fold (P < 0.02). OPG was expressed by 32% (+/-6.3) of osteoblasts increasing to 51% (+/-5.5) when cultured in the presence of megakaryocytes (P < 0.01) with a 1.63-fold increase in intensity of expression (P < 0.01). In contrast, osteoblasts cultured with megakaryocytes showed suppression of RANKL expression; 35.6% (+/-5.8) of osteoblasts cultured alone stained positively decreasing to 24.3% (+/-5.3) with a 1.6-fold diminished intensity of expression (P < 0.02). Osteoblasts co-cultured with CD61-negative cells showed no differences in collagen, OPG, or RANKL expression levels compared to osteoblasts cultured alone. mRNA data supported these findings with a 3.1-fold increase in Col 1A1 expression in megakaryocyte-treated cultures compared to controls (P < 0.02). Low-level OPG mRNA expression increased 8.14-fold in osteoblasts cultured in the presence of megakaryocytes (P < 0.01), while RANKL expression was suppressed 3.3-fold (P < 0.02). These results demonstrate that in vitro, megakaryocytes have direct effects on osteoblastic production of factors affecting both bone formation and resorption. These data provide further evidence that megakaryocytes may play an important role in bone remodeling.     

18F-fluoride Positron Emission Tomography Measurements of Regional Bone Formation in Hemodialysis Patients with Suspected Adynamic Bone Disease

¹⁸F-fluoride positron emission tomography (¹⁸F-PET) allows the assessment of regional bone formation and could have a role in the diagnosis of adynamic bone disease (ABD) in patients with chronic kidney disease (CKD). The purpose of this study was to examine bone formation at multiple sites of the skeleton in hemodialysis patients (CKD5D) and assess the correlation with bone biopsy. Seven CKD5D patients with suspected ABD and 12 osteoporotic postmenopausal women underwent an ¹⁸F-PET scan, and bone plasma clearance, K _i, was measured at ten skeletal regions of interest (ROI). Fifteen subjects had a transiliac bone biopsy following double tetracycline labeling. Two CKD5D patients had ABD confirmed by biopsy. There was significant heterogeneity in K _i between skeletal sites, ranging from 0.008 at the forearm to 0.028 mL/min/mL at the spine in the CKD5D group. There were no significant differences in K _i between the two study groups or between the two subjects with ABD and the other CKD5D subjects at any skeletal ROI. Five biopsies from the CKD5D patients had single tetracycline labels only, including the two with ABD. Using an imputed value of 0.3 μm/day for mineral apposition rate (MAR) for biopsies with single labels, no significant correlations were observed between lumbar spine K _i corrected for BMAD (K _i/BMAD) and bone formation rate (BFR/BS), or MAR. When biopsies with single labels were excluded, a significant correlation was observed between K _i/BMAD and MAR (r = 0.81, p = 0.008) but not BFR/BS. Further studies are required to establish the sensitivity of ¹⁸F-PET as a diagnostic tool for identifying CKD patients with ABD.