Clinical characteristics of pregnancy and lactation associated osteoporosis: An online survey study.

Pregnancy and lactation associated osteoporosis is a rare and often severe osteoporosis presentation. Little information is available about etiology, clinical characteristics, risk factors and predictors of severity. Using an anonymized questionnaire, we defined clinical characteristics and potential risk factors for disease severity in PLO including primiparity, heparin exposure and celiac disease. PURPOSE: Pregnancy and lactation associated osteoporosis (PLO) is a rare form of early-onset osteoporosis in which young women present with fractures, usually multiple vertebral fractures, during late pregnancy or lactation. Little information is available about etiology, clinical characteristics, risk factors and predictors of disease severity. METHODS: PLO patients were recruited to complete an anonymized online questionnaire. Disease severity was defined as total number of fractures during or after the first pregnancy associated with a fracture(s). Analyses related disease severity to potential predictors including diseases/conditions or medication exposures. RESULTS: 177 completed surveys were received between 5/29/2018 and 1/12/2022. Average age at initial PLO fracture event was 32 ± 5 years. The majority were primiparous with singleton pregnancy and 79% fractured during lactation. Subjects reported 4.7 ± 2.7 total PLO fractures, with 48% reporting ≥ 5 fractures. Vertebral fractures, reported by 164/177 responders (93%), were the most common fracture type. Conditions and medications most commonly reported included vitamin D deficiency, amenorrhea unrelated to pregnancy, nephrolithiasis, celiac disease (CD), oral steroid use, heparin products during pregnancy and progestin only contraceptive after pregnancy. CD and heparins exposure during pregnancy were significantly related to disease severity. CONCLUSION: This is the largest study characterizing clinical features of PLO to date. The large number of participants and broad range of clinical and fracture characteristics queried has yielded novel information on the characteristics of PLO and potential risk factors for its severity, including primiparity, exposure to heparin and CD. These findings provide important preliminary data that can help target future mechanistic investigations.

Smoking Is Associated with Sex-Specific Effects on Bone Microstructure in Older Men and Women.

BACKGROUND: Smoking is a risk factor for fracture, but the mechanism by which smoking increases fracture risk is unclear. METHODS: Musculoskeletal health was compared with dual energy X-ray absorptiometry (DXA), high resolution peripheral quantitative computed tomography (HR-pQCT), trabecular bone score, and vertebral fracture assessment in current and past smokers and nonsmokers from a multiethnic study of adults ≥ age 65. Skeletal indices were adjusted for age and weight. RESULTS: Participants (n = 311) were mean age (±SD) 76.1 ± 6.5 years, mostly female (66.0%) and non-white (32.7% black/39.4% mixed race/26.3% white). Mean pack-years was 34.6 ± 20.4. In men (n = 106), weight and BMI were lower (both p < 0.05) in current vs past smokers. Male smokers consumed half the calcium of never and past smokers. BMD by DXA did not differ by smoking status at any skeletal site in either sex. Current male smokers had 13.5%-15.3% lower trabecular bone score vs never and past smokers (both p < 0.05). By HR-pQCT, trabecular volumetric BMD was 26.6%-30.3% lower and trabeculae were fewer, thinner and more widely spaced in male current vs past and never smokers at the radius (all p < 0.05). Cortical indices did not differ. Tibial results were similar, but stiffness was also 17.5%-22.2% lower in male current vs past and never smokers (both p< 0.05). In women, HR-pQCT trabecular indices did not differ, but cortical porosity was almost twice as high in current vs never smokers at the radius and 50% higher at the tibia (both p < 0.05). CONCLUSIONS: In summary, current smoking is associated with trabecular deterioration at the spine and peripheral skeleton in men, while women have cortical deficits. Smoking may have sex-specific skeletal effects. The consistent association with current, but not past smoking, suggests the effects of tobacco use may be reversible with smoking cessation.

Occult urolithiasis in asymptomatic primary hyperparathyroidism.

OBJECTIVE: Recent international guidelines suggest renal imaging to detect occult urolithiasis in all patients with asymptomatic primary hyperparathyroidism (PHPT), but data regarding their prevalence and associated risk factors are limited. We evaluated the prevalence and risk factors for occult urolithiasis. METHODS: Cross-sectional analysis of 96 asymptomatic PHPT patients from a university hospital in the United States with and without occult nephrolithiasis. RESULTS: Occult urolithiasis was identified in 21% of patients. Stone formers had 47% higher 24-hour urinary calcium excretion (p = 0.002). Although available in only a subset of patients (n = 28), activated vitamin D [1,25(OH)2D] was 29% higher (p = 0.02) in stone formers. There was no difference in demographics, BMI, calcium or vitamin D intake, other biochemistries, renal function, BMD, or fractures. Receiver operating characteristic curves indicated that urinary calcium excretion and 1,25(OH)2D had an area under the curve of 0.724 (p = 0.003) and 0.750 (p = 0.04), respectively. A urinary calcium threshold of >211mg/day provided a sensitivity of 84.2% and a specificity of 55.3% while a 1,25(OH)2D threshold of >91pg/mL provided a sensitivity and specificity of 62.5% and 90.0% respectively for the presence of stones. CONCLUSION: Occult urolithiasis is present in about one-fifth of patients with asymptomatic PHPT and is associated with higher urinary calcium and 1,25(OH)2D. Given that most patients will not have occult urolithiasis, targeted imaging in those most likely to have occult stones rather than screening all asymptomatic PHPT patients may be useful. The higher sensitivity of urinary calcium versus 1,25(OH)2D suggests screening those with higher urinary calcium may be an appropriate approach.

Bisphosphonates Maintain BMD after Sequential Teriparatide and Denosumab in Premenopausal Women with Idiopathic Osteoporosis.

CONTEXT: We previously reported that sequential teriparatide followed by denosumab substantially increases BMD in premenopausal idiopathic osteoporosis (PremenIOP). OBJECTIVE: To determine whether administration of bisphosphonates after denosumab cessation is associated with stable BMD in PremenIOP. DESIGN: Open-label extension study. PARTICIPANTS: 24 PremenIOP Teriparatide-Denosumab Study participants. INTERVENTIONS: Oral alendronate (ALN), 70mg weekly, or IV zoledronic acid (ZOL), 5mg once (patient choice), was administered 7 months (M) after final denosumab dose. OUTCOMES: BMD by DXA and serum C-telopeptide (CTX) q6M; vertebral fracture assessment (VFA) and HR-pQCT q12M. RESULTS: 24 women with PremenIOP (aged 43 ± 8 years), severely affected with low trauma adult fractures (range 0-12; 9 with vertebral fractures) and/or very low BMD, had large BMD increases on sequential teriparatide-denosumab (spine: 25 ± 9%; total hip: 11 ± 6%). During the Bisphosphonate Extension, mean BMD and CTX changes in the entire group were small and not statistically significant at 6 or 12M.Women choosing ZOL (n = 6) versus ALN (n = 18) did not differ by baseline age, BMI, fractures, BMD, or CTX. On ZOL, there were small LSBMD declines and CTX increases, particularly between 6M and 12M, while greater stability was observed on ALN.Changes in BMD and CTX did not differ by duration of denosumab (36M vs <36M) or between 20 women who remained premenopausal and 4 who transitioned into menopause. Higher pre-teriparatide CTX, likely reflecting baseline remodeling status, predicted more spine and hip bone loss. No new vertebral (clinical or VFA screening) or non-vertebral fractures occurred. CONCLUSION: BMD remained stable in women with PremenIOP who received bisphosphonates after sequential teriparatide-denosumab therapy.

Fractures in women with type 2 diabetes are associated with marked deficits in cortical parameters and trabecular plates.

The basis for increased fracture risk in type 2 diabetes (T2DM) is not well understood. In this multi-ethnic, population-based study (n = 565), we investigated bone microstructure, trabecular plate/rod morphology and mineralization in women with T2DM (n = 175) with and without fracture using a second-generation HRpQCT and individual trabecula segmentation and mineralization (ITS; ITM). Covariate-adjusted aBMD was 3.0-6.5% higher at all sites (all p < 0.005) in T2DM versus controls. By HRpQCT, T2DM had higher covariate-adjusted trabecular vBMD (5.3-6.4%) and number (3.8-5.1%) and greater cortical area at the radius and tibia. Covariate-adjusted cortical porosity was 10.0% higher at the tibia only in T2DM versus controls, but failure load did not differ. Among women with T2DM, those with adult atraumatic fracture (n = 59) had 5.2-8.5% lower adjusted aBMD at all sites by DXA compared to those without fracture (n = 103). By HRpQCT, those with fracture had lower adjusted total vBMD and smaller cortical area (10.2-16.1%), lower cortical thickness (10.5-15.8%) and lower cortical vBMD associated with 18.1% and 17.2% lower failure load at the radius and tibia respectively (all p < 0.05); plate volume and thickness were 5.7% and 4.7% lower respectively (p < 0.05) while rod volume fraction was 12.8% higher in the fracture group at the tibia only. Sodium glucose cotransporter 2 inhibitor users (SGLT2i; n = 19), tended to have lower radial rod tissue mineral density by ITS (p = 0.06). GLP1 agonist users (n = 19) had trabecular deficits at both sites and higher cortical porosity and larger pores at the distal tibia. In summary, T2DM is associated with increased cortical porosity while those with T2DM and fracture have more marked cortical deficits and fewer trabecular plates associated with lower failure load.

Reasons for increased fracture risk in type 2 diabetes (T2DM) are not well-understood. We used a multi-ethnic, population-based cohort (n = 565), to study bone structure in women with T2DM (n = 175) using advanced imaging and analysis techniques. Participants with T2DM tended to have higher bone density and better structure by dual energy x-ray absorptiometry and high resolution peripheral quantitative computed tomography respectively at the radius and tibia; only cortical porosity was higher (worse) in participants with diabetes compared to those without diabetes but there was no difference in bone strength. Participants with T2DM and fracture had lower cortical parameters and bone strength compared with participants with T2DM without fracture at both sites. In summary, T2DM is associated with increased cortical porosity while those with T2DM and fracture have more marked cortical deficits associated with lower failure load.

Skeletal Microstructure in Caribbean Hispanic Women.

Hispanic individuals are underrepresented in skeletal research. Bone mineral density (BMD) and fracture data are conflicting. We investigated skeletal health in elderly Caribbean Hispanic (HW), non-Hispanic white (NHW), and non-Hispanic black (NHB) women in a population-based study in New York City. We utilized high-resolution peripheral quantitative CT (HRpQCT), dual-energy X-ray absorptiometry (DXA), and finite element analysis (FEA). Of 442, 48.4% were HW, 21.3% NHW, and 30.3% NHB. Adjusted analyses are shown. Compared to NHW, HW had 8.5% (p < 0.01) lower spine areal BMD (aBMD) and 5.1% lower trabecular bone score (TBS). The frequency of morphometric vertebral fractures did not differ between HW and NHW. By HRpQCT, HW had 2.9% higher cortical (Ct) volumetric BMD (vBMD), 7.9% greater Ct area (Ct.Ar) and 9.4% greater Ct thickness (Ct.Th) at the radius compared to NHW. Results were similar at the tibia but trabecular microstructure tended to be worse. Ultimately, failure load (FL) did not differ between HW and NHW at either site. aBMD was 3.8% to 11.1% lower at the spine, femoral neck, and radius in HW compared to NHB (all p < 0.001) and vertebral fractures were twice as common. Compared to NHB, HW had 7.7% to 10.3% lower Ct.Ar at both the radius and tibia as well as 8.4% lower total vBMD, 6.3% lower trabecular number, and 10.3% lower Ct.Th at the tibia associated with 18.2% and 12.5% lower FL at both sites, respectively. In conclusion, HW had lower spine aBMD and TBS versus NHW women, whereas microstructural differences at the radius and tibia were small and not associated with differences in FL. In contrast, HW had lower aBMD, as well as deteriorated radial and tibial microstructure associated with worse FL compared to NHB women. Our results provide insight into racial/ethnic differences in skeletal health, adding to data that may be used to improve osteoporosis screening and treatment in HW. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Bone microstructure in proton pump inhibitor users.

OBJECTIVES: We assessed skeletal microstructure and stiffness in proton pump inhibitor (PPI) users compared to non-users with high resolution peripheral quantitative computed tomography (HRpQCT) and microfinite element analysis (µFEA) and other modalities. Relationships between PPI dose/frequency and bone parameters were evaluated. METHODS: We cross-sectionally assessed skeletal health in 601 older (≥age 65 years) adults (130 PPI users and 471 non-users) participating in a multi-ethnic population-based study of aging. RESULTS: PPI users tended to have more comorbidities and take more medications than non-users. Female PPI users (n = 100) were more likely to be non-Caucasian, shorter with higher BMI, and more likely to have diabetes, lower physical activity and be using anti-depressants and thiazide diuretics compared to non-users (n = 302). Male PPI users (n = 30) were more likely to have liver disease than non-users (n = 169). In women, historical fractures (53.0 % vs. 43.4 %, p = 0.05) and falls (38 % vs. 26.8 %, p = 0.04) tended to be more frequent in PPI users compared to non-users. Number of falls was higher in women reporting daily rather than intermittent PPI use (1.8/year vs. 1.0/year, p < 0.001). In women, there were no differences in any HRpQCT or µFEA parameter. By HRpQCT, covariate-adjusted cortical volumetric bone density (Ct.vBMD) was 4.2 % lower in male PPI users vs. non-users at the tibia (p = 0.04), but this did not result in reduced stiffness. There were no other differences by HRpQCT at the tibia or radius. CONCLUSIONS: PPI use was not associated with altered skeletal microstructure or stiffness in elderly men and women. The results do not support a relationship between PPI use and microstructure.

Teriparatide Followed by Denosumab in Premenopausal Idiopathic Osteoporosis: Bone Microstructure and Strength by HR-pQCT.

Premenopausal women with idiopathic osteoporosis (PreMenIOP) have marked deficits in skeletal microstructure. We have reported that sequential treatment with teriparatide and denosumab improves central skeletal bone mineral density (BMD) by dual-energy X-ray absorptiometry and central QCT in PreMenIOP. We conducted preplanned analyses of high-resolution peripheral quantitative computed tomography (HR-pQCT) scans from teriparatide and denosumab extension studies to measure effects on volumetric BMD (vBMD), microarchitecture, and estimated strength at the distal radius and tibia. Of 41 women enrolled in the parent teriparatide study (20 mcg daily), 34 enrolled in the HR-pQCT study. HR-pQCT participants initially received teriparatide (N = 24) or placebo (N = 10) for 6 months; all then received teriparatide for 24 months. After teriparatide, 26 enrolled in the phase 2B denosumab extension (60 mg q6M) for 24 months. Primary outcomes were percentage change in vBMD, microstructure, and stiffness after teriparatide and after denosumab. Changes after sequential teriparatide and denosumab were secondary outcomes. After teriparatide, significant improvements were seen in tibial trabecular number (3.3%, p = 0.01), cortical area and thickness (both 2.7%, p < 0.001), and radial trabecular microarchitecture (number: 6.8%, thickness: 2.2%, separation: -5.1%, all p < 0.02). Despite increases in cortical porosity and decreases in cortical density, whole-bone stiffness and failure load increased at both sites. After denosumab, increases in total (3.5%, p < 0.001 and 3.3%, p = 0.02) and cortical vBMD (1.7% and 3.2%; both p < 0.01), and failure load (1.1% and 3.6%; both p < 0.05) were seen at tibia and radius, respectively. Trabecular density (3.5%, p < 0.001) and number (2.4%, p = 0.03) increased at the tibia, while thickness (3.0%, p = 0.02) increased at the radius. After 48 months of sequential treatment, significant increases in total vBMD (tibia: p < 0.001; radius: p = 0.01), trabecular microstructure (p < 0.05), cortical thickness (tibia: p < 0.001; radius: p = 0.02), and whole bone strength (p < 0.02) were seen at both sites. Significant increases in total vBMD and bone strength parameters after sequential treatment with teriparatide followed by denosumab support the use of this regimen in PreMenIOP. © 2022 American Society for Bone and Mineral Research (ASBMR).

Changes in Bone Quality after Treatment with Etelcalcetide.

INTRODUCTION: Secondary hyperparathyroidism is associated with osteoporosis and fractures. Etelcalcetide is an intravenous calcimimetic for the control of hyperparathyroidism in patients on hemodialysis. Effects of etelcalcetide on the skeleton are unknown. METHODS: In a single-arm, open-label, 36-week prospective trial, we hypothesized that etelcalcetide improves bone quality and strength without damaging bone-tissue quality. Participants were 18 years or older, on hemodialysis ≥1 year, without calcimimetic exposure within 12 weeks of enrollment. We measured pretreatment and post-treatment areal bone mineral density by dual-energy X-ray absorptiometry, central skeleton trabecular microarchitecture by trabecular bone score, and peripheral skeleton volumetric bone density, geometry, microarchitecture, and estimated strength by high-resolution peripheral quantitative computed tomography. Bone-tissue quality was assessed using quadruple-label bone biopsy in a subset of patients. Paired t tests were used in our analysis. RESULTS: Twenty-two participants were enrolled; 13 completed follow-up (mean±SD age 51±14 years, 53% male, and 15% White). Five underwent bone biopsy (mean±SD age 52±16 years and 80% female). Over 36 weeks, parathyroid hormone levels declined 67%±9% ( P < 0.001); areal bone mineral density at the spine, femoral neck, and total hip increased 3%±1%, 7%±2%, and 3%±1%, respectively ( P < 0.05); spine trabecular bone score increased 10%±2% ( P < 0.001); and radius stiffness and failure load trended to a 7%±4% ( P = 0.05) and 6%±4% increase ( P = 0.06), respectively. Bone biopsy demonstrated a decreased bone formation rate (mean difference -25±4 µ m 3 / µ m 2 per year; P < 0.01). CONCLUSIONS: Treatment with etelcalcetide for 36 weeks was associated with improvements in central skeleton areal bone mineral density and trabecular quality and lowered bone turnover without affecting bone material properties. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: The Effect of Etelcalcetide on CKD-MBD (Parsabiv-MBD), NCT03960437.

Thiazide use and skeletal microstructure: Results from a multi-ethnic study.

Background: Thiazide diuretics, a commonly used class of anti-hypertensives, have been associated with increased areal bone mineral density (aBMD). Data regarding effects on fracture are conflicting and no information is available regarding effects on skeletal microstructure and mechanical competence. Methods: We compared skeletal microstructure, volumetric BMD (vBMD), stiffness and prevalent fractures in current thiazide diuretic users and non-users from a population-based multiethnic cohort of elderly adults age ≥ 65 years (N = 599) with high resolution peripheral quantitative computed tomography (HR-pQCT) and micro-finite element analysis. Results: Female current thiazide diuretic users had higher weight and BMI and were more likely to be non-Caucasian compared to non-users. There were no differences in age, historical fractures or falls between female users and non-users. Female thiazide users tended to have lower calcium and vitamin d intake compared to non-users. After adjusting for age, weight, race and other covariates, 1/3-radius mean aBMD by dual energy x-ray absorptiometry (DXA) was 3.2% (p = 0.03) higher in female users vs. non-users. By HRpQCT, adjusted mean cortical vBMD was 2.4% (p = 0.03) higher at the radius in female users vs. non-users, but there was no difference in stiffness. DXA results were similar in the subset of Black females. There was no difference in any adjusted aBMD or cortical skeletal parameters by DXA or HRpQCT respectively in males. Conclusions: Thiazide use was associated with a modestly higher aBMD at the predominantly cortical 1/3-radius site and radial cortical vBMD by HRpQCT in females. The effect on cortical bone may offer skeletal benefits in women taking thiazides for other indications such as hypertension, hypercalciuria or recurrent nephrolithiasis.

Bone and fat hormonal crosstalk with antiretroviral initiation.

BACKGROUND: Bone mineral density (BMD) loss and fat gain is common in people living with HIV (PLWH), particularly after initiating combination antiretroviral therapy (cART). Given the close metabolic interaction between bone and fat, we tested the hypotheses that changes in bone-derived hormones are associated with fat accumulation and changes in fat-derived hormones are associated with BMD loss following cART initiation. METHODS: HIV-seropositive subjects (n = 15) initiating fixed dose cART of tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/FTC/EFV) underwent dual X-ray absorptiometry (DXA) assessment pre-cART and again 12-months post-cART initiation. DXA-derived measurements included BMD at the lumbar spine, femoral neck, total hip, and trochanter and the trunk and total fat. Serum undercarboxylated osteocalcin (ucOCN), sclerostin, lipocalin-2, leptin, and adiponectin were measured pre and post-cART. Spearman's rank-order correlations assessed the cross-sectional associations between hormones and bone and fat mass pre- and post-cART. Linear regression models adjusting for baseline bone or fat mass assessed the association between hormone change and BMD/fat changes following cART initiation. RESULTS: ucOCN (p = 0.04) and lipocalin-2 (p = 0.03) increased post-cART while sclerostin, leptin, and adiponectin remained unchanged. BMD significantly decreased post-cART at all skeletal sites. Trunk and total fat increased post-cART but not significantly, while weight and BMI remained unchanged. In models adjusting for baseline BMD and fat mass, change in ucOCN was negatively associated with change in trunk (p = 0.008) and total fat (p = 0.01) and the change in leptin was positively associated with change in total hip (p = 0.03) and trochanteric BMD (p = 0.02). CONCLUSION: The current study demonstrates bone-fat crosstalk in cART initiating PLWH.

Denosumab After Teriparatide in Premenopausal Women With Idiopathic Osteoporosis.

CONTEXT: We have previously reported that teriparatide is associated with substantial increases in bone mineral density (BMD) at the lumbar spine (LS), total hip (TH), and femoral neck (FN) and small declines at the distal radius in 41 premenopausal women with idiopathic osteoporosis (IOP), all severely affected with low trauma fractures and/or very low BMD. Effects of teriparatide dissipate if not followed by antiresorptives. OBJECTIVE: To assess the effects of 12 and 24 months of denosumab in premenopausal women with IOP completing 24 months of teriparatide. METHODS: This was a preplanned phase 2B extension study. Premenopausal women with IOP who had completed a course of teriparatide received denosumab 60 mg every 6 months over 24 months. The main outcome measure was within-group change in BMD at the LS at 12 months. Secondary outcomes include change in 12-month BMD at other sites, 24-month BMD at all sites, trabecular bone score (TBS), and bone turnover markers (BTMs). RESULTS: After completing teriparatide, 32 participants took denosumab for 12 months and 29 for 24 months, with statistically significant increases in BMD at the LS (5.2 ± 2.6% and 6.9 ± 2.6%), TH (2.9 ± 2.4% and 4.6 ± 2.8%), and FN (3.0 ± 3.8% and 4.7 ± 4.9%). Over the entire 24-month teriparatide and 24-month denosumab treatment period, BMD increased by 21.9 ± 7.8% at the LS, 9.8 ± 4.6% at the TH, and 9.5 ± 4.7% at the FN (all P < .0001). TBS increased by 5.8 ± 5.6% (P < .001). Serum BTM decreased by 75% to 85% by 3 months and remained suppressed through 12 months of denosumab. Denosumab was generally well tolerated. CONCLUSION: These data support the use of sequential teriparatide and denosumab to increase BMD in premenopausal women with severe osteoporosis.

Spine Volumetric BMD and Strength in Premenopausal Idiopathic Osteoporosis: Effect of Teriparatide Followed by Denosumab.

CONTEXT: Premenopausal women with idiopathic osteoporosis (PreMenIOP) have marked deficits in bone density, microstructure, and strength. OBJECTIVE: To define effects of treatment with teriparatide followed by denosumab on lumbar spine (LS) volumetric bone mineral density (vBMD) and stiffness by finite element analysis assessed on central quantitative computed tomography (cQCT) scans. DESIGN, SETTINGS, AND PARTICIPANTS: Ancillary analysis of baseline, post-teriparatide, and post-denosumab cQCT scans from a randomized trial of 41 women allocated to teriparatide (20 mcg daily; n = 28) or placebo (n = 11). After 6 months, those on teriparatide continued for 18 months, and those on placebo switched to teriparatide for 24 months. After completing teriparatide, 33 enrolled in a Phase 2B extension with denosumab (60 mg every 6 months) for 12 months. MAIN OUTCOME MEASURES: Primary outcomes were percentage change from baseline in LS trabecular vBMD and stiffness after teriparatide and between end of teriparatide and completing denosumab. Percentage change from baseline in LS trabecular vBMD and stiffness after sequential teriparatide and denosumab were secondary outcomes. FINDINGS: There were large increases (all Ps < 0.001) in trabecular vBMD (25%), other vBMD parameters, and stiffness (21%) after teriparatide. Statistically significant increases in trabecular vBMD (10%; P < 0.001) and other vBMD parameters (P = 0.03-0.001) were seen after denosumab, while stiffness increased by 7% (P = 0.068). Sequential teriparatide and denosumab led to highly significant (all Ps < 0.001) increases LS trabecular vBMD (43%), other vBMD parameters (15-31%), and stiffness (21%). CONCLUSIONS: The large and statistically significant increases in volumetric density and stiffness after sequential treatment with teriparatide followed by denosumab are encouraging and support use of this regimen in PreMenIOP.

Whole exome sequencing reveals potentially pathogenic variants in a small subset of premenopausal women with idiopathic osteoporosis.

Osteoporosis in premenopausal women with intact gonadal function and no known secondary cause of bone loss is termed idiopathic osteoporosis (IOP). Women with IOP diagnosed in adulthood have profound bone structural deficits and often report adult and childhood fractures, and family history of osteoporosis. Some have very low bone formation rates (BFR/BS) suggesting osteoblast dysfunction. These features led us to investigate potential genetic etiologies of bone fragility. In 75 IOP women (aged 20-49) with low trauma fractures and/or very low BMD who had undergone transiliac bone biopsies, we performed Whole Exome Sequencing (WES) using our variant analysis pipeline to select candidate rare and novel variants likely to affect known disease genes. We ran rare-variant burden analyses on all genes individually and on phenotypically-relevant gene sets. For particular genes implicated in osteoporosis, we also assessed the frequency of all (including common) variants in subjects versus 6540 non-comorbid female controls. The variant analysis pipeline identified 4 women with 4 heterozygous variants in LRP5 and PLS3 that were considered to contribute to osteoporosis. All 4 women had adult fractures, and 3 women also had multiple fractures, childhood fractures and a family history of osteoporosis. Two women presented during pregnancy/lactation. In an additional 4 subjects, 4 different relevant Variants of Uncertain Significance (VUS) were detected in the genes FKBP10, SLC34A3, and HGD. Of the subjects with VUS, 2 had multiple adult fractures, childhood fractures, and presented during pregnancy/lactation, and 2 had nephrolithiasis. BFR/BS varied among the 8 subjects with identified variants; BFR/BS was quite low in those with variants that are likely to have adverse effects on bone formation. The analysis pipeline did not discover candidate variants in COL1A1, COL1A2, WNT, or ALPL. Although we found several novel and rare variants in LRP5, cases did not have an increased burden of common LRP5 variants compared to controls. Cohort-wide collapsing analysis did not reveal any novel disease genes with genome-wide significance for qualifying variants between controls and our 75 cases. In summary, WES revealed likely pathogenic variants or relevant VUS in 8 (11%) of 75 women with IOP. Notably, the genetic variants identified were consistent with the affected women's diagnostic evaluations that revealed histological evidence of low BFR/BS or biochemical evidence of increased bone resorption and urinary calcium excretion. These results, and the fact that the majority of the women had no identifiable genetic etiology, also suggest that the pathogenesis of and mechanisms leading to osteoporosis in this cohort are heterogeneous. Future research is necessary to identify both new genetic and non-genetic etiologies of early-onset osteoporosis.

Long-term Bone Loss and Deterioration of Microarchitecture After Gastric Bypass in African American and Latina Women.

CONTEXT: The prevalence of obesity is burgeoning among African American and Latina women; however, few studies investigating the skeletal effects of bariatric surgery have focused on these groups. OBJECTIVE: To investigate long-term skeletal changes following Roux-en-Y gastric bypass (RYGB) in African American and Latina women. DESIGN: Four-year prospective cohort study. PATIENTS: African American and Latina women presenting for RYGB (n = 17, mean age 44, body mass index 44 kg/m2) were followed annually for 4 years postoperatively. MAIN OUTCOME MEASURES: Dual-energy x-ray absorptiometry (DXA) measured areal bone mineral density (aBMD) at the spine, hip, and forearm, and body composition. High-resolution peripheral quantitative computed tomography measured volumetric bone mineral density (vBMD) and microarchitecture. Individual trabecula segmentation-based morphological analysis assessed trabecular morphology and connectivity. RESULTS: Baseline DXA Z-Scores were normal. Weight decreased ~30% at Year 1, then stabilized. Parathyroid hormone (PTH) increased by 50% and 25-hydroxyvitamin D was stable. By Year 4, aBMD had declined at all sites, most substantially in the hip. There was significant, progressive loss of cortical and trabecular vBMD, deterioration of microarchitecture, and increased cortical porosity at both the radius and tibia over 4 years. There was loss of trabecular plates, loss of axially aligned trabeculae, and decreased trabecular connectivity. Whole bone stiffness and failure load declined. Risk factors for bone loss included greater weight loss, rise in PTH, and older age. CONCLUSIONS: African American and Latina women had substantial and progressive bone loss, deterioration of microarchitecture, and trabecular morphology following RYGB. Further studies are critical to understand the long-term skeletal consequences of bariatric surgery in this population.

Current anti-depressant use is associated with cortical bone deficits and reduced physical function in elderly women.

BACKGROUND: Anti-depressants, particularly selective serotonin reuptake inhibitors (SSRIs), are associated with an increased risk of fracture. The mechanism is unclear and may be due to effects on bone metabolism, muscle strength, falls or other factors. It is unknown if serotonin norepinephrine reuptake inhibitors (SNRIs) have similar effects. METHODS: We compared musculoskeletal health in current female anti-depressant users and non-users from a population-based multiethnic (35.6% black, 22.3% white and 42.1% mixed) cohort study of adults ≥65 years old in New York (N = 195) using dual x-ray absorptiometry (DXA), trabecular bone score (TBS), vertebral fracture assessment (VFA), high resolution peripheral quantitative computed tomography (HR-pQCT), body composition, and grip strength. RESULTS: Current anti-depressant users were more likely to be white than non-white (OR 1.9, 95% CI 1.2-2.9) and were shorter than non-users, but there were no differences in age, weight, BMI, physical activity, calcium/vitamin D intake, falls or self-rated health. There were more pelvic fractures in current vs. non-users (7.1% vs. 0%, p = 0.04). Age- and weight-adjusted T-score by DXA was lower in current users at the 1/3-radius (-1.6 ± 1.1 vs. -1.0 ± 1.4, p = 0.04) site only. There was no difference in TBS, vertebral fractures or fat/lean mass by DXA. Age- and weight-adjusted grip strength was 13.3% lower in current users vs. non-users (p = 0.04). By HR-pQCT, age- and weight-adjusted cortical volumetric BMD (Ct. vBMD) was 4.8% lower in users vs. non-users at the 4% radius site (p = 0.007). A similar cortical pattern was seen at the proximal (30%) tibia. When assessed by anti-depressant class, deteriorated cortical microstructure was present only in SSRI users at the radius and only in SNRI users at the proximal tibia. CONCLUSIONS: Anti-depressant use is associated with cortical deterioration and reduced physical function, but effects may be class-specific. These findings provide insight into the mechanism by which anti-depressants may contribute to the increased fracture risk in older women.

Serum extracellular vesicles expressing bone activity markers associate with bone loss after HIV antiretroviral therapy.

OBJECTIVE: We tested whether bone-related extracellular vesicle phenotypes changed after initiating antiretroviral therapy (ART) and determined whether changes in levels of extracellular vesicles correlated with changes in bone mineral density (BMD). DESIGN: Extracellular vesicle phenotypes were measured in blinded serum samples from 15 adults with HIV at baseline, 1, 3, 6 and 12 months after ART initiation. Not all samples were available at each time point so we averaged early (TP1, 1-3 months) and late (TP2, 6-12 months) time points. METHODS: Extracellular vesicles were stained for osteocalcin (OC), RANKL (CD254), RANK (CD265), M-CSF (macrophage colony stimulating factor), and CD34. Serum OC, procollagen type I N-terminal propeptide (P1NP), and C-terminal telopeptide of type 1 collagen (CTx) were also measured. RESULTS: BMD significantly decreased from baseline to 12 months. Levels of OC+EVs, serum OC, serum P1NP, and CTx were significantly higher at early and late time points compared with baseline. Increases in EVs expressing OC, RANKL, RANK, and CD34 from baseline to TP1 were associated with decreases in total hip BMD from baseline to 12 months. Change in serum OC, P1NP, and CTx from baseline to TP1 or TP2 did not correlate with change in BMD. CONCLUSION: Early changes in extracellular vesicles expressing markers of bone activity were associated with total hip bone loss 12 months after ART initiation. These data suggest that serum extracellular vesicles may serve as novel biomarkers of bone remodeling. Future studies are required to determine if extracellular vesicles contribute to the effects of ART on changes in bone turnover markers and BMD.

Effect of vitamin D3 and calcium carbonate supplementation on muscle strength in postmenopausal women living with HIV.

BACKGROUND: Both falls and fractures are increased in older persons living with HIV (PLWH). Low serum total 25-hydroxyvitamin D (25-OHD) levels have been associated with falls, fractures and poor muscle strength. We hypothesized that vitamin D (VitD) supplementation would improve muscle strength in postmenopausal PLWH. METHODS: In a 12-month prospective, randomized, double-blind, study of 69 African American and Hispanic postmenopausal PLWH on antiretroviral therapy with 25-OHD ≥10 ng/ml and ≤32 ng/ml, we investigated the effects of daily low (1,000 IU; n=31) and moderate (3,000 IU; n=38) cholecalciferol doses on lean mass and strength. Change in lean body mass was assessed by dual-energy X-ray absorptiometry (DXA), and isometric and isokinetic muscle strength in the dominant lower extremity was assessed using the Biodex System 4 Pro. RESULTS: Mean age was 56 ±5 years, median CD4+ T-cell count 722 cells/mm3 and 74% had HIV RNA≤50 copies/ml. Serum 25-OHD did not differ at baseline, but was higher in the moderate than low VitD group at 6 and 12 months. In both groups, there were significant increases in lower extremity isokinetic torque, work and power at 12 months, with no change in lean mass. CONCLUSIONS: VitD supplementation was associated with a modest increase in lower extremity strength in postmenopausal PLWH, without a concomitant increase in muscle mass. Magnitude of increase in strength were similar with 3,000 IU and 1,000 IU daily. Future larger studies will be required to determine the optimal dose of VitD to improve muscle strength and to determine whether supplementation reduces the risk of falls and fractures in PLWH.

Abnormal microarchitecture and stiffness in postmenopausal women with isolated osteoporosis at the 1/3 radius.

BACKGROUND: Postmenopausal women with isolated osteoporosis at the 1/3 radius (1/3RO) present a therapeutic dilemma. Little is known about whether these patients have generalized skeletal fragility, and whether this finding warrants treatment. The aim of this study was to investigate the biochemical and microarchitectural phenotype of women with 1/3RO compared to women with classic postmenopausal osteoporosis by DXA at the spine and hip (PMO), and controls without osteoporosis at any site. METHODS: This cross-sectional study enrolled 266 postmenopausal women, who were grouped according to densitometric pattern. Subjects had serum biochemistries, areal BMD (aBMD) measured by DXA, trabecular and cortical vBMD, microarchitecture, and stiffness by high resolution peripheral QCT (HR-pQCT, voxel size ~82 µm) of the distal radius and tibia. RESULTS: Mean age was 68 ± 7 years. DXA T-Scores reflected study design. By HR-pQCT, 1/3RO had abnormalities at both radius and tibia compared to controls: lower total, cortical and trabecular vBMD, cortical thickness and trabecular number, higher trabecular separation and heterogeneity, and lower whole bone stiffness. In contrast, the magnitude and pattern of abnormalities in vBMD, microarchitecture and stiffness in 1/3RO were similar to those in PMO; the difference compared to controls was similar among the two groups. Serum calcium, creatinine, parathyroid hormone, 25-hydroxyvitamin D, and 24-hour urine calcium did not differ. CONCLUSIONS: Although aBMD appeared relatively preserved at the spine and hip by DXA, women with 1/3RO had significant microarchitectural and biomechanical deficits comparable to those in women with typical PMO. Further study is required to guide treatment decisions in this population.

Effect of Teriparatide on Bone Remodeling and Density in Premenopausal Idiopathic Osteoporosis: A Phase II Trial.

CONTEXT: Premenopausal women with idiopathic osteoporosis (IOP) have abnormal skeletal microarchitecture and variable tissue-level bone formation rate (BFR). OBJECTIVES: Compare 6 months (M) of teriparatide versus placebo on areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA), bone turnover markers (BTMs) and BFR at 3M by quadruple-labeled transiliac biopsy. Characterize 12M and 24M effects of teriparatide on aBMD and whether BTMs and BFR predict response. DESIGN: 6M phase 2 randomized controlled trial (RCT) followed by open extension. SETTING: Tertiary referral centers. PATIENTS: Premenopausal women with IOP. INTERVENTIONS: A total of 41 women were randomized to either teriparatide 20 mcg (n = 28) or placebo (n = 13). After 6M, those on placebo switched to teriparatide for 24M; those on teriparatide continued for 18M. MAIN OUTCOME MEASURES: 6M RCT: Between-group differences in lumbar spine (LS) aBMD (percent change from baseline), 3M BFR, and hypercalcemia. Open-label extension: Within-group change in LS aBMD over 12M and 24M. Secondary outcomes included aBMD change at other sites and relationship between BTMs, BFR, and changes in aBMD. FINDINGS: Over 6M, LS aBMD increased by 5.5% (95% CI: 3.83, 7.19) in teriparatide and 1.5% (95% CI: -0.73, 3.83) in placebo (P = 0.007). There were increases in 3M BTMs, and BFR (cancellous and endocortical BFR: between-groups P = 0.004). Over 24M, teriparatide increased LS aBMD by 13.2% (95% CI: 10.3, 16.2), total hip by 5.2% (95% CI: 3.7, 6.7) and femoral neck by 5.0% (95% CI: 3.2, 6.7; all P ≤ 0.001). Serum N-terminal propeptides of procollagen type 1 (P1NP) and 3M endocortical BFR were moderately associated with LS aBMD response. Teriparatide was well-tolerated. CONCLUSIONS: Teriparatide increased BFR and formation markers and was associated with marked aBMD improvements in most premenopausal women (82%) with IOP.