Background: Antiresorptive agents are widely used to treat osteoporosis. We report the results of a multinational randomized, double-blind study, in which postmenopausal women with osteoporosis were treated with alendronate for up to 10 years. Methods: The initial three-year phase of the study compared three daily doses of alendronate with placebo. Women in the original placebo group received alendronate in years 4 and 5 and then were discharged. Women in the original active-treatment groups continued to receive alendronate during the initial extension (years 4 and 5). In two further extensions (years 6 and 7, and 8 through 10), women who had received 5 mg or 10 mg of alendronate daily continued on the same treatment. Women in the discontinuation group received 20 mg of alendronate daily for two years and 5 mg daily in years 3, 4, and 5, followed by five years of placebo. Randomized group assignments and blinding were maintained throughout the 10 years. We report results for the 247 women who participated in all four phases of the study. Results: Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 13.7 percent at the lumbar spine (95 percent confidence interval, 12.0 to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval, 8.1 to 12.4 percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 percent), and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to 9.1 percent) as compared with base-line values; smaller gains occurred in the group given 5 mg daily. The discontinuation of alendronate resulted in a gradual loss of effect, as measured by bone density and biochemical markers of bone remodeling. Safety data, including fractures and stature, did not suggest that prolonged treatment resulted in any loss of benefit. Conclusions: The therapeutic effects of alendronate were sustained, and the drug was well tolerated over a 10-year period. The discontinuation of alendronate resulted in the gradual loss of its effects.

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Ten years' experience with alendronate for osteoporosis in postmenopausal women.

Although multiple hormones and cytokines regulate various aspects of osteoclast formation, the final two effectors are osteoprotegerin ligand (OPG-L)/osteoclast differentiation factor (ODF), a recently cloned member of the tumor necrosis factor superfamily, and macrophage colony-stimulating factor. OPG-L/ODF is produced by osteoblast lineage cells and exerts its biological effects through binding to its receptor, osteoclast differentiation and activation receptor (ODAR)/receptor activator of NF-kappa B (RANK), on osteoclast lineage cells, in either a soluble or a membrane-bound form, the latter of which requires cell-to-cell contact. Binding results in rapid differentiation of osteoclast precursors in bone marrow to mature osteoclasts and, at higher concentrations, in increased functional activity and reduced apoptosis of mature osteoclasts. The biological activity of OPG-L/ODF is neutralized by binding to osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF), a member of the TNF-receptor superfamily that also is secreted by osteoblast lineage cells. The biological importance of this system is underscored by the induction in mice of severe osteoporosis by targeted ablation of OPG/OCIF and by the induction of osteopetrosis by targeted ablation of OPG-L/ODF or overexpression of OPG/OCIF. Thus, osteoclast formation may be determined principally by the relative ratio of OPG-L/ODF to OPG/OCIF in the bone marrow microenvironment, and alterations in this ratio may be a major cause of bone loss in many metabolic disorders, including estrogen deficiency and glucocorticoid excess. That changes in but two downstream cytokines mediate the effects of large numbers of upstream hormones and cytokines suggests a regulatory mechanism for osteoclastogenesis of great efficiency and elegance.

The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption.

Noninvasive assessment of bone mineral and structure: state of the art.

Glucocorticoid-induced bone loss should be prevented, and if present, should be treated (Table 2). Supplementation with calcium and vitamin D at a dosage of 800 IU/day, or an activated form of vitamin D (e.g., alfacalcidiol at 1 microg/day or calcitriol at 0.5 microg/day), should be offered to all patients receiving glucocorticoids, to restore normal calcium balance. This combination has been shown to maintain bone mass in patients receiving long-term low-to-medium-dose glucocorticoid therapy who have normal levels of gonadal hormones. However, while supplementation with calcium and vitamin D alone generally will not prevent bone loss in patients in whom medium-to-high-dose glucocorticoid therapy is being initiated, supplementation with calcium and an activated form of vitamin D will prevent bone loss. There are no data available to support any conclusion about the antifracture efficacy of the combination of calcium supplementation plus an activated form of vitamin D. Antiresorptive agents are effective in the treatment of glucocorticoid-induced bone loss. All of these agents either prevent bone loss or modestly increase lumbar spine bone mass and maintain hip bone mass. While there are no randomized controlled trials of prevention of glucocorticoid-induced bone loss or radiographic vertebral fracture outcomes with HRT or testosterone, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered HRT. The bisphosphonates are effective for both the prevention and the treatment of glucocorticoid-induced bone loss. Large studies have demonstrated that bisphosphonates also reduce the incidence of radiographic vertebral fractures in postmenopausal women with glucocorticoid-induced osteoporosis. Treatment with a bisphosphonate is recommended to prevent bone loss in all men and postmenopausal women in whom long-term glucocorticoid treatment at > or =5 mg/day is being initiated, as well as in men and postmenopausal women receiving long-term glucocorticoids in whom the BMD T-score at either the lumbar spine or the hip is below normal. While there is little information on the prevention or treatment of bone loss in premenopausal women, these women, too, may lose bone mass if they are being treated with glucocorticoids, so prevention of bone loss with antiresorptive agents should be considered. If bisphosphonate therapy is being considered for a premenopausal woman, she must be counseled regarding use of appropriate contraception. The therapies to prevent or treat glucocorticoid-induced bone loss should be continued as long as the patient is receiving glucocorticoids. Data from large studies of anabolic agents (e.g., PTH) and further studies of combination therapy in patients receiving glucocorticoids are eagerly awaited so additional options will be available for the prevention of this serious complication of glucocorticoid treatment.

Recommendations for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

ContextOsteoporosis causes substantial morbidity and costs $13.8
billion annually in the United States. Measurement of bone mass by densitometry
is a primary part of diagnosing osteoporosis and deciding a preventive
treatment course. Bone mineral densitometry has become more widely available
and commonly used in practice.ObjectiveTo review evidence about the value of various clinical applications of bone densitometry.Data SourcesA MEDLINE search was performed to update previous meta-analyses of
the relationship between various measurements of bone density and risk of
vertebral and hip fracture. We used data from the prospective Study of
Osteoporotic Fractures to estimate risk of fracture from bone density and age
in postmenopausal women.Study Selection and Data ExtractionWhen available, meta-analyses and systematic reviews are emphasized in the review.Data SynthesisBone mineral density (BMD) predicts fracture and can be
used in combination with age to estimate absolute risk of fractures in
postmenopausal white women. Hip BMD predicts hip fracture more strongly than
other measurements of BMD. There are insufficient data to translate BMD results
into risk of fracture for men and nonwhite women. The benefits of treatments to
prevent fractures depend on BMD: women with osteoporosis have a greater risk of
fractures and greater benefit from treatments than women without osteoporosis.ConclusionsGuidelines based on systematic reviews and a
cost-effectiveness analysis have suggested that it is worthwhile to measure BMD
in white women older than 65 years and perhaps to use risk factors to select
younger postmenopausal women for densitometry. Other potential clinical
applications of BMD that have not yet been adequately studied include screening
men or nonwhite women, monitoring BMD in patients receiving treatment, and
using BMD to identify patients who should be evaluated for secondary causes of
osteoporosis.

https://jamanetwork.com/journals/jama/articlepdf/195421/JSR20013.pdf

Clinical use of bone densitometry: scientific review.

To determine whether simple measurements made on conventional radiographs of the hip could predict hip fractures, we obtained pelvic radiographs on 9704 white women age 65 or older. We analyze the radiographs of all 162 women who subsequently suffered a hip fracture and 162 randomly selected women who did not. Adjusting for age, four measurements independently predicted hip fractures: reduced thickness of the femoral shaft cortex (odds ratio 1.7 per standard deviation; 95% confidence interval 1.2, 2.3) and of the femoral neck cortex (1.4 per standard deviation; 1.0, 1.9), reduction in an index of tensile trabeculae (2.0 per unit; 1.4, 2.9), and wider trochanteric region (1.4 per standard deviation; 1.0, 2.0). The combination of these four measurements predicted hip fracture at least as strongly as did measurement of bone density of the femoral neck (areas of the receiver-operating characteristic curve = 0.81 and 0.80, respectively). We conclude that simple measurements made on pelvic radiographs predict hip fractures as well as bone density of the hip.

Prediction of hip fractures from pelvic radiographs: the study of osteoporotic fractures

Vertebral Fractures in Osteoporosis: A New Method for Clinical Assessment

We assessed the impact of various forms of spinal degenerative joint disease (DJD) on bone mineral density (BMD) measured by quantitative computed tomography (QCT) and dual X-ray absorptiometry (DXA) in a group of postmenopausal women. Lateral (T4-L4) and AP (L1-L4) spinal radiographs were reviewed for fracture and DJD in 209 women (mean age 62.6 +/- 6.7). The severity of DJD findings was graded as 0, 1, or 2 on the lumbar films, except for vertebral osteophytes which were graded from 0 to 3. Vertebral fractures were defined semiquantitatively as approximately 20% reduction in anterior, middle, or posterior vertebral height. BMD was measured in all subjects by QCT and DXA, including posteroanterior DXA (PA-DXA), lateral DXA (L-DXA) and midlateral DXA (mL-DXA). When BMD was measured by QCT and mL-DXA in the 168 women without fractures, no significant differences were found between women with and those without DJD. However, BMD by PA-DXA was significantly higher in women with DJD changes, particularly when osteophytes were present at the vertebral bodies or facet joints. BMD by L-DXA was less affected by DJD. For this measurement a significant increase in BMD was only noted in subjects with vertebral osteophytes. Multivariate analysis of variance (MANOVA) showed that BMD by QCT and mL-DXA was not affected by DJD. In contrast, for all women, BMD by PA- and L-DXA was affected more by DJD than by fracture status. Chi-square testing demonstrated no significant relationships between vertebral fractures and any of the DJD changes. We conclude that QCT and mL-DXA are superior to PA-DXA and L-DXA in detecting bone loss in patients with DJD. Thus, for these patients, BMD assessment by QCT or mL-DXA may be advisable.

Influence of degenerative joint disease on spinal bone mineral measurements in postmenopausal women.

We have evaluated the Lunar Expert-XL for standard bone mineral densitometry (BMD) and for morphometric imaging of the spine in the lateral projection. The short-term precision in vitro of the Expert-XL for BMD measurements was 0.7% for the Hologic and European spine phantoms, and the long-term stability (15-month) measurements had a 1.1% coefficient of variation. The precision in vivo for three operators examining a group of 10 premenopausal women was 0.9-1.5% for lumbar spine (L2-L4), 1.7-2.2% for the femoral neck, and 0.9% for the total hip region of interest. For a group of nine postmenopausal women, the lumbar spine, femoral neck, and total femur precision ranges were 2.0-2.4, 1.2-2.9, and 1.6-1.7% respectively. For L2-L4, BMD comparison between the Expert-XL and DPX-L yielded a correlation coefficient of r = 0.98, a slope of 0.86, and an intercept of 0.139 g/cm2. The femoral neck results were r = 0.92, slope = 1.00, and intercept = 0.03 g/cm2. In an evaluation of the Expert-XL for lateral morphometry, we employed a group of 16 postmenopausal women. Comparison of vertebral dimensions between the Expert-XL and radiographic morphometry showed strong agreement (r = 0.97), but the interobserver variability for vertebral height was higher for the Expert-XL than for radiographs (3-5% vs. 1-2%). In a subset of four women who had repeat scans, the interscan precision for measuring vertebral dimensions was 1.9, 4.1, and 43% for the L1-L4, T12-T8, and T7-T5 levels respectively. In the Expert-XL images, it was possible to identify clearly L4-T4 in 10 of 16 patients and L4-T6 in 15 of 16, indicating potential utility for vertebral fracture prescreening.

A preliminary evaluation of the lunar expert-XL for bone densitometry and vertebral morphometry.

Minimally anterolateral approach (MAA) and direct anterior approach (DAA) have been reported as beneficial for total hip arthroplasty (THA) due to their ability to reduce postoperative pain and lead to quicker rehabilitation by preserving muscle insertions. As there is an ongoing debate on the effect of these two approaches on early postoperative outcomes, this prospective study aimed to assess the difference in early clinical, radiological, and patient-reported outcomes between the two minimally invasive approaches.A total of 98 patients, 50 in the MAA group and 48 in the DAA group, were included in the study. Patients with complete data were evaluated preoperatively and postoperatively at 2, 6, and 12 weeks. Clinical measurements, including the ability to climb stairs and walk, 6-min walk test (6MWT), the Forgotten Joint Scale (FJS-12), Japanese Orthopedic Association (JOA) Hip scores, radiological evaluation, and complications were analyzed.There were no significant differences in clinical outcomes and implant alignments between MAA and DAA groups. In regards to patient-reported outcomes, the FJS-12 was significantly higher in the MAA group compared to group DAA at 2 and 6 weeks postoperatively. However, there was no significant difference in the FJS-12 between the two groups 12 weeks after surgery. The differences also included shorter operative times (62.4 ± 9.05 min vs. 71 ± 8.01 min), less blood loss (132.6 ± 43.31 ml vs. 159.23 ± 37.25 ml), lower Hb drop (29.56 ± 8.02 g/L vs. 36.4 ± 7.12 g/L), and fewer blood transfusions in the MAA group (4.0% vs. 18.8%). The incidence of the lateral femoral cutaneous nerve (LFCN) neuropraxia after surgery was 7 (14.6%) in the DAA group and 0 in the MAA group. One fracture was found in each group and managed conservatively.MAA and DAA approach yielded excellent and similar early clinical outcomes. However, better patient-reported outcomes could be achieved by MAA THA. The MAA resulted in a safer approach associated with shorter operative times, less blood loss, lower Hb drop, fewer blood transfusions, and LFCN neuropraxia than DAA. A longer follow-up is needed to further examine differences between these procedures. 

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Minimally invasive anterolateral approach versus direct anterior approach total hip arthroplasty in the supine position: a prospective study based on early postoperative outcomes

Jiao Li

Papers

Prediction of hip fractures from pelvic radiographs: the study of osteoporotic fractures

Vertebral Fractures in Osteoporosis: A New Method for Clinical Assessment

Influence of degenerative joint disease on spinal bone mineral measurements in postmenopausal women.

A preliminary evaluation of the lunar expert-XL for bone densitometry and vertebral morphometry.

Minimally invasive anterolateral approach versus direct anterior approach total hip arthroplasty in the supine position: a prospective study based on early postoperative outcomes