Zoledronic acid sequential to teriparatide may promote greater inhibition of bone resorption than zoledronic acid alone.

Background: Teriparatide (TPTD) should be followed by an antiresorptive to maximize bone mineral density gain and anti-fracture protection. Infrequent zoledronic acid (ZOL) administration has demonstrated effectiveness. The duration of ZOL effect following TPTD is unknown. Objective: To evaluate the effect of ZOL on bone resorption marker in a post-TPTD versus ZOL-alone scenario in osteoporotic patients. Design: Retrospective cohort study. Methods: Patients treated with TPTD followed by ZOL (TPTD-ZOL) or with a single ZOL infusion were identified in the database of a tertiary referral center. Clinical and laboratory data, including C-terminal telopeptide of type I collagen (CTX) following ZOL treatment, were compared. Results: Twenty-six patients (93% women) treated with TPTD-ZOL and 41 with ZOL were comparable in age (median 70.1 versus 69.6 years, p = 0.6) and sex. Timing of CTX measurement post-ZOL was the same, median 1.0 year. CTX was lower following TPTD-ZOL (median 142.1 versus 184.2 pg/mL, p = 0.005). In a multivariable regression model (controlled for baseline characteristics), pretreatment with TPTD strongly predicted CTX <150 pg/mL, 1 year following ZOL (odds ratio = 7.5, 95% CI 1.3-58.1, p = 0.03). In a subgroup with sequential CTX measurements following one ZOL, significantly lower levels persisted in the TPTD-ZOL group for a median of 4.4 years follow-up. Conclusion: ZOL-administered sequential to TPTD yielded deeper and more prolonged bone resorption suppression than ZOL alone. Prospective data are needed to confirm whether in a sequential treatment scenario, subsequent ZOL dosing interval should be less frequent.

Romosozumab improves lumbar spine bone mass and bone strength parameters relative to alendronate in postmenopausal women: results from the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial.

The Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial (NCT01631214; https://clinicaltrials.gov/ct2/show/NCT01631214) showed that romosozumab for 1 year followed by alendronate led to larger areal bone mineral density (aBMD) gains and superior fracture risk reduction versus alendronate alone. aBMD correlates with bone strength but does not capture all determinants of bone strength that might be differentially affected by various osteoporosis therapeutic agents. We therefore used quantitative computed tomography (QCT) and finite element analysis (FEA) to assess changes in lumbar spine volumetric bone mineral density (vBMD), bone volume, bone mineral content (BMC), and bone strength with romosozumab versus alendronate in a subset of ARCH patients. In ARCH, 4093 postmenopausal women with severe osteoporosis received monthly romosozumab 210 mg sc or weekly oral alendronate 70 mg for 12 months, followed by open-label weekly oral alendronate 70 mg for ≥12 months. Of these, 90 (49 romosozumab, 41 alendronate) enrolled in the QCT/FEA imaging substudy. QCT scans at baseline and at months 6, 12, and 24 were assessed to determine changes in integral (total), cortical, and trabecular lumbar spine vBMD and corresponding bone strength by FEA. Additional outcomes assessed include changes in aBMD, bone volume, and BMC. Romosozumab caused greater gains in lumbar spine integral, cortical, and trabecular vBMD and BMC than alendronate at months 6 and 12, with the greater gains maintained upon transition to alendronate through month 24. These improvements were accompanied by significantly greater increases in FEA bone strength (p < 0.001 at all time points). Most newly formed bone was accrued in the cortical compartment, with romosozumab showing larger absolute BMC gains than alendronate (p < 0.001 at all time points). In conclusion, romosozumab significantly improved bone mass and bone strength parameters at the lumbar spine compared with alendronate. These results are consistent with greater vertebral fracture risk reduction observed with romosozumab versus alendronate in ARCH and provide insights into structural determinants of this differential treatment effect. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Opportunistic screening for osteoporosis and osteopenia by routine computed tomography scan: A heterogeneous, multiethnic, middle-eastern population validation study.

PURPOSE: We aimed define thresholds for HU values observed on opportunistic CT scans that suggest abnormal bone mineral density (BMD) in a heterogeneous Middle Eastern population. METHODS: Consecutive patients who had undergone CT and dual-energy X-ray absorptiometry (DXA) test of the lumbar spine within 6 months were included in this retrospective study. Hounsfield units (HU) on lateral lumbar spine CT and BMD at the spine and hip on DXA were compared. Potential HU thresholds suggestive of abnormal BMD were established using receiver operating characteristic (ROC) analysis. RESULTS: 246 patients (mean age of 64 ±â€¯11.6 years; 83 % female) were included. On DXA, 27 % had osteoporosis, 56 % had osteopenia, and 17 % had normal BMD. To distinguish osteoporosis from non-osteoporosis (osteopenia, normal BMD), a threshold of HU160 had sensitivity 95 % and the balanced threshold was HU121 (sensitivity 74 %, specificity 61 %). To distinguish normal from abnormal BMD (osteoporosis, osteopenia), a threshold of HU110 had specificity 93 % and the balanced threshold was HU149 (sensitivity 76 %, specificity 74 %). CONCLUSIONS: In a heterogeneous Middle-Eastern population, our study supports the reported correlation between HU values on lumbar spine CT and BMD on DXA. In this population, HU > 160 correlates with low probability of osteoporosis on DXA, and screening examination is not warranted unless a vertebral fracture is detected; for HU ≤ 110 there is high probability of abnormal (osteoporosis or osteopenia) BMD, DXA examination is warranted; Finally, for HU 110-160, there is an intermediate chance of abnormal BMD, DXA examination may be warranted in specific patients with other risk factors.

2013 International Society for Clinical Densitometry Position Development Conference: Task Force on Normative Databases.

Following the standard protocol for development of Official Positions for the International Society for Clinical Densitometry, the Expert Panel heard the report and recommendations from the Task Force on Normative Databases; using the RAND methodology, agreement was reached on the following statements: 1. Manufacturers should continue to use their own databases for the lumbar spine as the reference standard for T-scores. 2. Manufacturers should continue to use National Health and Nutrition Examination Survey III data as the reference standard for femoral neck and total hip T-scores. 3. If local reference data are available, they should be used to calculate only Z-scores but not T-scores. 4. A uniform Caucasian (non-race adjusted) female reference database should be used to calculate T-scores for men of all ethnic groups.

The outcome of surgically treated femur fractures associated with long-term bisphosphonate use.

INTRODUCTION: Bisphosphonates (BPs) evolved as the mainstay for the treatment of osteoporosis, reducing the incidence of fractures. Recently several publications described the occurrence of low-energy subtrochanteric and femoral shaft fractures associated with long-term BP use. The aim of this study was to describe the outcome of surgically treated femur fractures associated with prolonged BP use. PATIENTS: Fifteen patients suffering from 17 atypical femoral fragility fractures associated with long-term (>3 years) BP use were located. Data included fracture type, time of BP use, last bone mineral density DEXA scores for the femoral neck and spine, type of surgery, and the need for revision. RESULTS: Fourteen female patients and one male patient were identified. The median age was 73 years (range, 51-80 years). The mean BP use was 7.8 years (range, 4-13 years). Fourteen patients had low-energy traumatic femoral shaft (proximal and distal) or low subtrochanteric fractures. The mean lumbar spine (for 13 patients) bone mineral density T-score was -3.0, whereas mean femoral neck T-score was -1.8 with only three patients in the osteoporotic range.Fracture healing after the first procedure for patients treated with nails was 54%, with 46% of patients requiring revision surgery. These included nail dynamization, exchange nailing, and one revision to a blade plate. All of these eventually healed. CONCLUSIONS: BP-related fractures are a recently described phenomenon. Despite initial osteoporosis, the DEXA scan may appear outside the osteoporotic range for the femoral neck in these patients. In addition, a much higher failure rate with intramedullary nailing requiring revision surgery may occur with these patients.

Significant and continuous improvement in bone mineral density among type 1 Gaucher disease patients treated with velaglucerase alfa: 69-month experience, including dose reduction.

Since bone pathology is a major concern in type 1 Gaucher disease (GD1), we evaluated bone mineral density (BMD) in adults receiving velaglucerase alfa in the seminal Phase I/II and extension trial. Ten treatment-naïve symptomatic patients with GD1 (four men, six women; median age 35years, range 18-62years) were included; of these, four patients were receiving bisphosphonates at enrollment. Using WHO criteria to classify the lumbar spine (LS) and femoral neck (FN) BMD T-scores, respectively, one (10%) and four (40%) patients had osteoporosis; eight (80%) and five (50%) had osteopenia; and one each (10%) was in the normal range, at baseline. By Month 69, two LS and one FN osteopenic patients normalized and one FN osteoporotic patient became osteopenic; change was seen only in patients not receiving bisphosphonates. Significant improvements in BMD Z-scores were seen at the LS by Month 24 and at the FN by Month 33 and were continuous thereafter. In linear mixed models, Z-scores were significantly lower than the reference population at baseline and improved significantly with treatment (LS and FN both P<0.01); analysis of the subgroup of patients not receiving bisphosphonates showed similar results. In conclusion, in this small cohort, velaglucerase alfa was associated with clinically meaningful and statistically significant LS and FN BMD improvements as early as Month 24 (LS) and 33 (FN), despite dose reduction and significant baseline skeletal pathology. These results suggest that velaglucerase alfa may hold promise in the management of skeletal pathology associated with GD1.

Equipment modification is associated with fewer stress fractures in female Israel border police recruits.

PURPOSE: The study was planned to assess whether combat equipment weight reduction would lead to a reduction in the incidence of stress fractures in female border police infantry recruits taking a 4-month course of basic combat training. METHOD: 213 female border police recruits, 18-19 years of age, undergoing 16 weeks of basic combat training with lighter rifle and lighter closely fitted combat vest, (total 9.4 kg) were followed prospectively for stress fracture (SFx) incidence, compared to a historical control group of 1,210 recruits who trained with traditional equipment (12.5 kg). RESULTS: Equipment modification was associated with a significant reduction in SFx from 18.3% in the control group to 8.0% in the intervention group (p < 0.0001). CONCLUSIONS: This study implies that equipment weight reduction may achieve a significant effect in SFx reduction, Approximating fighting gear to body center of gravity may enhance this effect.

Molecular aspects of osteopathy in type 1 Gaucher disease: correlation between genetics and bone density.

Bone-related complications in Gaucher disease are considered to be poorly responsive to specific enzyme replacement therapy. Polymorphisms of candidate genes associated with low bone density were investigated to see whether they are correlated with bone mineral density (BMD) and bone involvement in Gaucher disease. Genotyping for polymorphisms in candidate genes (interleukins 1alpha and 1beta, interleukin-1 receptor antagonist; cytochrome P450; collagen 1A1; low-density Lipoprotein Receptor; bone morphogenic protein 4; vitamin D receptor; and estrogen receptor 2beta) were performed using standard methodologies. BMD was measured by dual energy X-ray absorptiometry (DXA). One hundred and ninety-four patients and 100 controls were genotyped for the above polymorphisms. Thirteen haplotypes were obtained, with several correlations with BMD in patients; also, a haplotype (T889-T3954-C511-240VNTR of IL1) was significantly correlated with T-scores and Z-score for femur neck and lumbar spine (p = 0.01) in patients. Haplotypes of bone-specific candidate genes associated with BMD may predict severity of these features in Gaucher disease.

Effects of estradiol and raloxifene on arterial thrombosis in ovariectomized mice.

OBJECTIVE: The effects of estrogen and selective estrogen receptor modulators (eg, raloxifene) on arterial thrombosis are not well defined. This study assessed the manner and mechanism by which estrogen and raloxifene affect homeostatic pathways in ovariectomized mice after acute arterial injury. DESIGN: Female mice (3 weeks old) underwent ovariectomy or sham operation. Five days after surgery, mice were assigned to treatment with estradiol (5.3 nmol/kg), raloxifene (2.7 micromol/kg), or placebo (n = 10-12/group). The biological effects of both treatments were assessed by measurements of bone mass and the degree of uterine atrophy. After 4 months of therapy, carotid artery thrombosis was induced by photochemical injury, and the time to vascular occlusion was measured. RESULTS: Both treatments increased bone mineral density (4.1%-7.85%). Reversal of macroscopic uterine atrophy was observed only in estrogen-treated mice. Ovariectomized mice had a shorter time to occlusion compared with sham-operated mice (70.8 +/- 7.4 vs 103 +/- 11.3 min), suggesting accelerated thrombosis. Both estradiol and raloxifene significantly inhibited intra-arterial thrombosis in ovariectomized mice, prolonging the time to occlusion to 136.33 +/- 13.5 and 141.43 +/- 9.26 min, respectively. Cyclooxygenase-2 levels in the lung tissue were significantly increased by both raloxifene and estradiol with endothelial nitric oxide synthase expression being unaltered. Platelet adhesion (measured by surface coverage under a shear rate of 1,800 s for 2 min) was significantly reduced in ovariectomized animals, being 4.63% +/- 1.47%, 5.78% +/- 1.58%, and 10.04% +/- 1.33% for raloxifene, estradiol, and placebo, respectively. CONCLUSIONS: Ovariectomy amplifies thrombosis. We found that 4 months of treatment with both estradiol and raloxifene attenuates intravascular thrombosis. The antithrombotic effect was accompanied by increased expression of cyclooxygenase-2 and suppression of platelet surface adhesion.

High prevalence of iron deficiency and anemia in female military recruits.

Iron deficiency anemia has long been known to impair physical and mental performance. Iron deficiency itself, even without anemia, may also cause such an effect. Similar to female athletes, women in active military units may have increased risks for iron deficiency and its detrimental effects. Female recruits were screened for anemia and iron store status, and a questionnaire on lifestyle habits and menstruation was completed. Iron depletion (serum ferritin level of <20 microg/L) was found for 77% of study participants. Iron deficiency (ferritin level of <12 microg/L and transferrin saturation of <15%) was found for 15% of study participants. Anemia was found for 24% of subjects, and iron deficiency anemia was found for 10% of subjects. High prevalence of iron depletion, iron deficiency, anemia, and iron deficiency anemia was found among female recruits intended for active military duty. Therefore, a recommendation can be made to screen such female recruits for anemia and iron stores.

Serum levels of osteoprotegerin and osteoprotegerin polymorphisms in Gaucher disease.

Bone involvement in Gaucher disease causes disability and reduced quality of life; loss of function and pain are important indications for enzyme replacement therapy. The purpose of this study was to ascertain whether osteoprotegerin (OPG), which decreases osteoclast activity, is indicative of incipient bone involvement by comparing OPG serum levels to Gaucher disease severity (SSI) and bone mineral density (BMD), and to correlate bone and disease markers to OPG polymorphisms: OPG1-2(A163G), OPG3-4(T129C) and OPG5-6(C1217T). Of 554 patients, 173 Ashkenazi Jewish patients with non-neuronopathic Gaucher disease were enrolled and 32 healthy Ashkenazi Jews served as controls. Serum OPG levels were detected by enzyme-linked immunosorbent assay and BMD was obtained by dual X-ray absorptiometry. OPG polymorphisms were determined in 63 randomly chosen patients. Serum OPG values for patients were not greater than in controls, but showed a statistically significant trend to increase with age (P = 0.057). No correlation existed between OPG levels and BMD or with genotype or other disease markers. A significant correlation was noted between OPG5-6 genotype and SSI. A significant difference was found between the allele distributions of each OPG polymorphism when compared with Caucasians and Ashkenazi Jews. OPG levels probably do not predict BMD in Gaucher disease and hence are not indicative of osteoporosis in Gaucher disease.

Treatment preference and tolerability with alendronate once weekly over a 3-month period: an Israeli multi-center study.

BACKGROUND AND AIMS: Osteoporosis is a chronic condition requiring long-term treatment, for which compliance is not easy to achieve. 70 mg of alendronate once weekly (alendronate OW) provides equivalent efficacy to treatment with 10 mg of alendronate once a day (alendronate OD); however, there are relatively few data regarding patient and physician preferences for once-weekly vs daily dosing. The aim of this study was to measure compliance, convenience, tolerance and relative preference of alendronate OW treatment among post-menopausal women with osteoporosis and physician satisfaction, compared with previous treatment with alendronate OD. METHODS: This open-label, prospective multi-center trial was conducted at 14 hospitals and 150 primary-care community clinics in Israel. Post-menopausal osteoporotic women (n = 3710), who had been treated for at least 1 month with alendronate OD during the preceding year, were treated with alendronate OW for 12 weeks. Convenience, satisfaction, tolerance and relative preference of alendronate OW during the trial, compared with past experience with alendronate OD, were recorded. RESULTS: Overall, 96% of the patients preferred the alendronate OW regimen to the 10-mg daily dosage. Nearly all (98%) the patients who completed 12 weeks of treatment, including 77% of patients who had previously discontinued daily treatment due to intolerance, were willing to continue the alendronate OW regimen. Patient-reported compliance with dosing instructions was over 98%. Alendronate OW was well tolerated; only 2.8% of patients discontinued, due to adverse events. Physicians were highly satisfied with the once-weekly dosing regimen, and recommended continued treatment with alendronate OW for 99% of the patients. CONCLUSIONS: The majority of post-menopausal women with osteoporosis, including those who were previously intolerant to alendronate OD, preferred alendronate OW to the once-daily dosing regimen. It is important to consider patient preference when selecting the appropriate treatment for osteoporosis.

Bone density changes with enzyme therapy for Gaucher disease.

Gaucher disease is the most common lysosomal storage disease. Enzyme replacement therapy engenders improvement in hematological and visceral parameters; however, improvement in bone density (BMD) with treatment has not been confirmed. This study presents follow-up of BMD in the first ten patients in Israel treated with low-dose recombinant enzyme for up to 108 months. BMD at femoral neck and lumbar spine was determined by dual-energy X-ray absorptiometry (DEXA) at the start of the trial, after 3-6 months, after 18-24 months, and at the most recent follow-up. BMD in all patients was very low at onset and never normalized. There was a decrease in BMD in all patients at 3-6 months. Older patients (four women, two men; >30 years of age) showed some improvement in BMD during treatment. Younger patients (four females; 18-23 years of age) did not show a statistically significant improvement. These findings might reflect the failure of patients with Gaucher disease to achieve expected peak bone density at appropriate chronological milestones despite treatment. Nonetheless, the z-scores of the older patients were better than those of the younger patients, implying some catch-up period. Yet, some patients with Gaucher disease evince rapid onset of osteoporosis in early adulthood. Enzyme treatment per se, as well as attendant improved well-being and increased physical activity, may induce amelioration in BMD at this later stage. One may consider adding anti-osteoporosis therapy in young adults to induce earlier "catch up" to peak bone mass, and then enzyme replacement in later adulthood to prevent decrements in bone mass related to Gaucher cell infiltration.

Decreased bone density in carriers and patients of an Israeli family with the osteoporosis-pseudoglioma syndrome.

BACKGROUND: The osteoporosis-pseudoglioma syndrome is a rare autosomal recessive disorder characterized by severe juvenile-onset osteoporosis and congenital or early-onset blindness. Other manifestations include muscular hypotonia, ligamentous laxity, mild mental retardation and seizures. The gene responsible was recently identified to be the low density lipoprotein receptor-related family member LRP5 on chromosome 11q11-12. OBJECTIVE: To measure bone density in two siblings with the OPPG syndrome as well as in their family members (parents and siblings). METHODS: Bone mineral density was determined in the lumbar spine (antero-posterior), femoral neck, two-thirds distal forearm (> 95% cortical bone) and ultradistal forearm (predominantly trabecular bone) by dual-energy X-ray absorptiometry. RESULTS: The studies revealed osteoporotic changes both in the patients and the carriers. CONCLUSION: The findings demonstrate that OPPG carriers have reduced bone mass, which is a risk factor for development of early osteoporotic changes.