The cost-effectiveness of osteoporosis medications for preventing periprosthetic fractures following femoral neck fracture indicated hip arthroplasty: a break-even analysis.

Osteoporosis treatment following arthroplasty for femoral neck fracture (FNF) is associated with lower rates of periprosthetic fracture (PPF). Our study evaluated the economic viability of treatment in patients following arthroplasty and demonstrates that treatment with oral bisphosphonates can be cost-effective in preventing PPF. INTRODUCTION: Osteoporosis treatment following arthroplasty for femoral neck fracture (FNF) is associated with lower rates of periprosthetic fracture (PPF). Although cost-effective in reducing the rate of secondary fragility fracture, the economic viability of osteoporosis treatment in preventing PPF has not been evaluated. Therefore, the purpose of this study is to use a break-even analysis to determine whether and which current osteoporosis medications are cost-effective in preventing PPF following arthroplasty for FNFs. METHODS: Three-year average cost of osteoporosis medication (oral bisphosphonates, estrogen hormonal therapy, intravenous (IV) bisphosphonates, denosumab, teriparatide, and abaloparatide), costs of PPF care, and PPF rates in patients who underwent hip arthroplasty for FNFs without osteoporosis treatment were used to perform a break-even analysis. The absolute risk reduction (ARR) related to osteoporosis treatment and sensitivity analyses were used to evaluate the cost-effectiveness of this intervention and break-even PPF rates. RESULTS: Oral bisphosphonate therapy following arthroplasty for hip fractures would be economically justified if it prevents one out of 56 PPFs (ARR, 1.8%). Given the current cost and incidence of PPF, overall treatment can only be economically viable for PPF prophylaxis if the 3-year costs of these agents are less than $1500. CONCLUSION: The utilization of lower cost osteoporosis medications such as oral bisphosphonates and estrogen hormonal therapy as PPF prophylaxis in this patient population would be economically viable if they reduce the PPF rate by 1.8% and 1.5%, respectively. For IV bisphosphonates and newer agents to be economically viable as PPF prophylaxis in the USA, their costs need to be significantly reduced.

Safety and Immune Responses Following Anti-PD-1 Monoclonal Antibody Infusions in Healthy Persons With Human Immunodeficiency Virus on Antiretroviral Therapy.

Background: T cells in people with human immunodeficiency virus (HIV) demonstrate an exhausted phenotype, and HIV-specific CD4+ T cells expressing programmed cell death 1 (PD-1) are enriched for latent HIV, making antibody to PD-1 a potential strategy to target the latent reservoir. Methods: This was a phase 1/2, randomized (4:1), double-blind, placebo-controlled study in adults with suppressed HIV on antiretroviral therapy with CD4+ counts ≥350 cells/µL who received 2 infusions of cemiplimab versus placebo. The primary outcome was safety, defined as any grade 3 or higher adverse event (AE) or any immune-related AE (irAE). Changes in HIV-1-specific polyfunctional CD4+ and CD8+ T-cell responses were evaluated. Results: Five men were enrolled (median CD4+ count, 911 cells/µL; median age, 51 years); 2 received 1 dose of cemiplimab, 2 received 2 doses, and 1 received placebo. One participant had a probable irAE (thyroiditis, grade 2); another had a possible irAE (hepatitis, grade 3), both after a single low-dose (0.3 mg/kg) infusion. The Safety Monitoring Committee recommended no further enrollment or infusions. All 4 cemiplimab recipients were followed for 48 weeks. No other cemiplimab-related serious AEs, irAEs, or grade 3 or higher AEs occurred. One 2-dose recipient of cemiplimab had a 6.2-fold increase in polyfunctional, Gag-specific CD8+ T-cell frequency with supportive increases in plasma HIV RNA and decreases in total HIV DNA. Conclusions: One of 4 participants exhibited increased HIV-1-specific T-cell responses and transiently increased HIV-1 expression following 2 cemiplimab infusions. The occurrence of irAEs after a single, low dose may limit translating the promising therapeutic results of cemiplimab for cancer to immunotherapeutic and latency reversal strategies for HIV. Clinical Trials Registration. NCT03787095.

Increased Advanced Glycation Endproducts, Stiffness, and Hardness in Iliac Crest Bone From Postmenopausal Women With Type 2 Diabetes Mellitus on Insulin.

Individuals with type 2 diabetes mellitus (T2DM) have a greater risk of bone fracture compared with those with normal glucose tolerance (NGT). In contrast, individuals with impaired glucose tolerance (IGT) have a lower or similar risk of fracture. Our objective was to understand how progressive glycemic derangement affects advanced glycation endproduct (AGE) content, composition, and mechanical properties of iliac bone from postmenopausal women with NGT (n = 35, age = 65 ± 7 years, HbA1c = 5.8% ± 0.3%), IGT (n = 26, age = 64 ± 5 years, HbA1c = 6.0% ± 0.4%), and T2DM on insulin (n = 25, age = 64 ± 6 years, HbA1c = 9.1% ± 2.2%). AGEs were assessed in all samples using high-performance liquid chromatography to measure pentosidine and in NGT/T2DM samples using multiphoton microscopy to spatially resolve the density of fluorescent AGEs (fAGEs). A subset of samples (n = 14 NGT, n = 14 T2DM) was analyzed with nanoindentation and Raman microscopy. Bone tissue from the T2DM group had greater concentrations of (i) pentosidine versus IGT (cortical +24%, p = 0.087; trabecular +35%, p = 0.007) and versus NGT (cortical +40%, p = 0.003; trabecular +35%, p = 0.004) and (ii) fAGE cross-link density versus NGT (cortical +71%, p < 0.001; trabecular +44%, p < 0.001). Bone pentosidine content in the IGT group was lower than in the T2DM group and did not differ from the NGT group, indicating that the greater AGE content observed in T2DM occurs with progressive diabetes. Individuals with T2DM on metformin had lower cortical bone pentosidine compared with individuals not on metformin (-35%, p = 0.017). Cortical bone from the T2DM group was stiffer (+9%, p = 0.021) and harder (+8%, p = 0.039) versus the NGT group. Bone tissue AGEs, which embrittle bone, increased with worsening glycemic control assessed by HbA1c (Pen: R2  = 0.28, p < 0.001; fAGE density: R2  = 0.30, p < 0.001). These relationships suggest a potential mechanism by which bone fragility may increase despite greater tissue stiffness and hardness in individuals with T2DM; our results suggest that it occurs in the transition from IGT to overt T2DM. © 2022 American Society for Bone and Mineral Research (ASBMR).

SHBG, Bone Mineral Density, and Physical Function Among Injection Drug Users With and Without HIV and HCV.

CONTEXT: Sex hormone-binding globulin (SHBG) is a glycoprotein that regulates the bioavailability of sex hormones and is higher in people with HIV (PWH) and hepatitis C virus (HCV). SHBG is associated with aging-related diseases, including osteoporosis and frailty in the general population. However, the relationship between SHBG concentration and bone mineral density (BMD) and physical function among PWH and HCV is unclear. OBJECTIVE: This study aimed to evaluate the association between chronic infection with HIV and HCV and SHBG, and to assess the relationship of circulating SHBG concentrations with low BMD, physical function impairment, and frailty. METHODS: A cross-sectional study was conducted of 278 HCV-exposed (HCV antibody positive) adults enrolled with and without HIV and HCV from the AIDS Linked to the IntraVenous Experience cohort study into 4 groups: HCV-/HIV-, HCV-/HIV+, HCV+/HIV-, and HCV+/HIV+. We evaluated the association between SHBG concentrations and grip strength, gait speed, Short Physical Performance Battery score, frailty (Fried Frailty Phenotype), and BMD (lumbar spine, total hip, and femoral neck T-score) by using adjusted multivariable regression stratified by sex. RESULTS: SHBG concentrations were higher in women, in those with HIV RNA greater than 400 copies/mL (P = .02) and HCV RNA greater than 15 IU/mL (P < .001). In adjusted models, higher SHBG concentrations among women were statistically significantly associated with lower grip strength (-0.43 [95% CI, -0.77 to -0.081] kg/10 nmol/L, P < .05), higher odds of frailty (odds ratio, 1.49 [95% CI, 1.07 to 2.08], P < .05), and lower T-scores at the lumbar spine (-0.070 [95% CI, -0.15 to -0.001] SD/10 nmol/L T-score BMD, P < .05). Similar associations were not observed among men. CONCLUSION: Higher SHBG concentrations are associated with the presence of HIV and HCV viremia. Among women, but not men, higher SHBG concentrations were associated with lower grip strength, higher odds of frailty, and lower lumbar spine BMD. The underlying mechanisms of these associations require further investigation.

Advanced glycation endproducts and bone quality: practical implications for people with type 2 diabetes.

PURPOSE OF REVIEW: Individuals with type 2 diabetes (T2D) are at increased risk of fracture, often despite normal bone density. This observation suggests deficits in bone quality in the setting of abnormal glucose homeostasis. The goal of this article is to review recent developments in our understanding of how advanced glycation end products (AGEs) are incorporated into the skeleton with resultant deleterious effects on bone health and structural integrity in patients with T2D. RECENT FINDINGS: The adverse effects of skeletal AGE accumulation on bone remodeling and the ability of the bone to deform and absorb energy prior to fracture have been demonstrated both at the bench as well as in small human studies; however, questions remain as to how these findings might be better explored in large, population-based investigations. SUMMARY: Hyperglycemia drives systemic, circulating AGE formation with subsequent accumulation in the bone tissue. In those with T2D, studies suggest that AGEs diminish fracture resistance, though larger clinical studies are needed to better define the direct role of longstanding AGE accumulation on bone strength in humans as well as to motivate potential interventions to reverse or disrupt skeletal AGE deposition with the goal of fracture prevention.

Impact of Hormonal Therapies for Treatment of Hormone-Dependent Cancers (Breast and Prostate) on the Cardiovascular System: Effects and Modifications: A Scientific Statement From the American Heart Association.

Cardiovascular disease and cancer are the leading causes of death in the United States, and hormone-dependent cancers (breast and prostate cancer) are the most common noncutaneous malignancies in women and men, respectively. The hormonal (endocrine-related) therapies that serve as a backbone for treatment of both cancers improve survival but also increase cardiovascular morbidity and mortality among survivors. This consensus statement describes the risks associated with specific hormonal therapies used to treat breast and prostate cancer and provides an evidence-based approach to prevent and detect adverse cardiovascular outcomes. Areas of uncertainty are highlighted, including the cardiovascular effects of different durations of hormonal therapy, the cardiovascular risks associated with combinations of newer generations of more intensive hormonal treatments, and the specific cardiovascular risks that affect individuals of various races/ethnicities. Finally, there is an emphasis on the use of a multidisciplinary approach to the implementation of lifestyle and pharmacological strategies for management and risk reduction both during and after active treatment.

Bone Tissue Composition in Postmenopausal Women Varies With Glycemic Control From Normal Glucose Tolerance to Type 2 Diabetes Mellitus.

The risk of fragility fracture increases for people with type 2 diabetes mellitus (T2DM), even after controlling for bone mineral density, body mass index, visual impairment, and falls. We hypothesize that progressive glycemic derangement alters microscale bone tissue composition. We used Fourier-transform infrared (FTIR) imaging to analyze the composition of iliac crest biopsies from cohorts of postmenopausal women characterized by oral glucose tolerance testing: normal glucose tolerance (NGT; n = 35, age = 65 ± 7 years, HbA1c = 5.8 ± 0.3%), impaired glucose tolerance (IGT; n = 26, age = 64 ± 5 years, HbA1c = 6.0 ± 0.4%), and overt T2DM on insulin (n = 25, age = 64 ± 6 years, HbA1c = 9.13 ± 0.6). The distributions of cortical bone mineral content had greater mean values (+7%) and were narrower (-10%) in T2DM versus NGT groups (p < 0.05). The distributions of acid phosphate, an indicator of new mineral, were narrower in cortical T2DM versus NGT and IGT groups (-14% and -14%, respectively) and in trabecular NGT and IGT versus T2DM groups (-11% and -10%, respectively) (all p < 0.05). The distributions of crystallinity were wider in cortical NGT versus T2DM groups (+16%) and in trabecular NGT versus T2DM groups (+14%) (all p < 0.05). Additionally, bone turnover was lower in T2DM versus NGT groups (P1NP: -25%, CTx: -30%, ucOC: -24%). Serum pentosidine was similar across groups. The FTIR compositional and biochemical marker values of the IGT group typically fell between the NGT and T2DM group values, although the differences were not always statistically significant. In summary, worsening glycemic control was associated with greater mineral content and narrower distributions of acid phosphate, an indicator of new mineral, which together are consistent with observations of lower turnover; however, wider distributions of mineral crystallinity were also observed. A more mineralized, less heterogeneous tissue may affect tissue-level mechanical properties and in turn degrade macroscale skeletal integrity. In conclusion, these data are the first evidence of progressive alteration of bone tissue composition with worsening glycemic control in humans. © 2020 American Society for Bone and Mineral Research (ASBMR).

Vertebral bone quality score predicts fragility fractures independently of bone mineral density.

BACKGROUND: Current evidence suggests that dual-energy x-ray absorptiometry (DXA) scans, the conventional method defining osteoporosis, is underutilized and, when used, may underestimate patient risk for skeletal fragility. It has recently been suggested that other imaging modalities may better estimate bone quality, such as the magnetic resonance imaging (MRI)-based vertebral bone quality (VBQ) score which also may assess vertebral compression fracture risk in patients with spine metastases. PURPOSE: To evaluate whether VBQ score is predictive of fragility fractures in a population with pre-existing low bone density and at high-risk for fracture. STUDY DESIGN/SETTING: Retrospective single-center cohort. PATIENT SAMPLE: Patients followed at a metabolic bone clinic for osteopenia and/or osteoporosis. OUTCOME MEASURES: Radiographically-documented new-onset fragility fracture. METHODS: Patients with a DXA and MRI scans at the time of consultation and ≥2-year follow-up were included. Details were gathered about patient demographics, health history, current medication use, and serological studies of kidney function and bone turnover. For each patient, VBQ score was calculated using T1-weighted lumbar MRI images. Univariable and multivariable analyses were used to identify the independent predictors of a new fragility fracture. To support the construct validity of VBQ, patient VBQ scores were compared to those in a cohort of 45 healthy adults. RESULTS: Seventy-two (39.1%) study participants suffered fragility fractures, the occurrence of which was associated with higher VBQ score (3.50 vs. 3.01; p<.001), chronic glucocorticoid use (30.6% vs. 15.2%; p=.014), and a history of prior fragility fracture (36.1% vs. 21.4%; p=.030). Mean VBQ score across all patients in the study cohort was significantly higher than the mean VBQ score in the healthy controls (p<.001). In multivariable analysis, new-onset fracture was independently associated with history of prior fracture (OR=6.94; 95% confidence interval [2.48-19.40]; p<.001), higher VBQ score (OR=2.40 per point; [1.30-4.44]; p=.003), higher body mass index (OR=1.09 per kg/m²; [1.01-1.17]; p=.03), and chronic glucocorticoid use (OR=2.89; [1.03-8.17]; p=0.043). Notably, DXA bone mineral density (BMD) was not found to be significantly predictive of new-onset fractures in the multivariable analysis (p=.081). CONCLUSIONS: Here we demonstrate the novel, MRI-derived VBQ score is both an independent predictor of fragility fracture in at-risk patients and a superior predictor of fracture risk than DXA-measured BMD. Given the frequency with which MRIs are obtained by patients undergoing spine surgery consultation, we believe the VBQ score could be a valuable tool for estimating bone quality in order to optimize the management of these patients.

Diabetes and Bone Fragility: SGLT2 Inhibitor Use in the Context of Renal and Cardiovascular Benefits.

PURPOSE OF REVIEW: Type 2 diabetes mellitus (T2DM) has been shown to negatively impact bone quality and increase fracture risk. While the pathophysiology of bone fragility in T2DM is not clear and likely multifactorial, medications used to treat T2DM are increasingly scrutinized for their potential role in aberrant bone metabolism. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are gaining popularity in patients with T2DM. In addition to lowering blood glucose, there is evidence that these drugs offer cardiac and renal benefit to individuals with T2DM, leading to FDA-approved indications for use in at-risk individuals. At the same time, there remain concerns that SGLT2 inhibitors, specifically canagliflozin, have adverse effects on bone metabolism and increase fracture risk in T2DM. This review seeks to further clarify the impact of these agents on the skeleton. RECENT FINDINGS: SGLT2 inhibitors may indirectly disrupt calcium and phosphate homeostasis, contribute to weight loss, and cause hypotension, resulting in bone mineral density (BMD) losses and increased falls. The true long-term impact of SGLT2 inhibitors on the diabetic skeleton is still unclear; this review summarizes the results in studies investigating the impact of SGLT2 inhibitors on fracture risk in T2DM. Whereas studies performed with dapagliflozin and empagliflozin have not shown an increased risk of bone fractures compared with placebo, some studies have shown increased markers of bone turnover and reduced bone mineral density with canagliflozin treatment. While an increased fracture risk was observed with canagliflozin in the CANVAS trial (HR 1.26; 95% CI 1.04, 1.52), an increased risk was not seen in the CANVAS-R (HR 0.86) or CREDENCE (HR 0.98) trials. There is substantial evidence of the cardiac and renal protective benefits of SGLT2 inhibitors. There does not appear to be an increased fracture risk with the use of dapagliflozin or empagliflozin. Given the possible association between canagliflozin and adverse bone outcomes described in CANVAS, canagliflozin use should be pursued in individuals with T2DM only after careful consideration of the individual's skeletal risk.

Hypoglycemic risk exposures in relation to low serum glucose values in ambulatory patients.

This study aimed to correlate hypoglycemic risk exposures (HREs) with low blood glucose value (BGV) in ambulatory patients to inform selection of a glucose critical action value (CAV).This was a retrospective study of ambulatory patients with at least 1 serum glucose ≤70 mg/dL obtained at 2 laboratories within the Johns Hopkins Health System over 3.8 years. Multivariable logistic regression was used to evaluate association of BGV cut-offs of <60, <54, <50, and <45 mg/dL with HREs. HREs were classified as "high hypoglycemic risk" (HHR), "moderate hypoglycemic risk" (MHR), "low hypoglycemic risk" (LHR), and "no hypoglycemic risk" (NHR).A total of 5404 patient samples of BG ≤70 mg/dL were analyzed, of which 30.3%, 23.2%, 28.5%, 18.0% occurred in NHR, LHR, MHR, and HHR groups, respectively. An inverse relationship was noted between BGV cut-offs and HHR, but no association was observed for LHR or MHR. After adjusting for age, sex, and race, there was an inverse association between BG thresholds and the odds of HHR. For classification of HHR, BGV cut-offs of <60, <54, <50, and <45 mg/dL correctly classified 71.2%, 69.8%, 68.8%, and 67.2% of BG samples, achieved false-positive rates of 13.6%, 4.7%, 1.7%, and 0.5% and positive likelihood ratios of 3.3, 6.0, 11.2, and 23.4, respectively.Nearly 70% of low BGVs occurred in patients with at least 1 HRE, but only ∼20% occurred in HHR patients. Given their high positive likelihood ratios, BGVs <54 or <50 mg/dL are reasonable candidates for CAVs that would allow sufficient clinician response time while minimizing false-positive alerts.

A Multidisciplinary Toxicity Team for Cancer Immunotherapy-Related Adverse Events.

BACKGROUND: Immune checkpoint inhibitors (ICIs) may cause immune-related adverse events (irAEs). Methods to obtain real-time multidisciplinary input for irAEs that require subspecialist care are unknown. This study aimed to determine whether a virtual multidisciplinary immune-related toxicity (IR-tox) team of oncology and medicine subspecialists would be feasible to implement, be used by oncology providers, and identify patients for whom multidisciplinary input is sought. PATIENTS AND METHODS: Patients treated with ICIs and referred to the IR-tox team in August 2017 through March 2018 were identified. Feasibility was defined as receipt of electronic referrals and provision of recommendations within 24 hours of referral. Use was defined as the proportion of referring providers who used the team's recommendations, which was determined through a postpilot survey. Demographics and tumor, treatment, and referral data were collected. Patient features and irAE associations were analyzed. RESULTS: The IR-tox team was found to be feasible and used: 117 referrals from 102 patients were received in 8 months, all providers received recommendations within 24 hours, 100% of surveyed providers used the recommendations, and 74% changed patient management based on IR-tox team recommendations. Referrals were for suspected irAEs (n=106; 91%) and suitability to treat with ICIs (n=11; 10%). In referred patients, median age was 64 years, 54% were men, 13% had prior autoimmunity, and 46% received ICI combinations versus monotherapy (54%). The most commonly referred toxicities were pneumonitis (23%), arthritis (16%), and dermatitis (15%); 15% of patients had multisystem toxicities. Multiple referrals were more common in those treated with combination ICIs (odds ratio [OR], 6.0; P=.035) or with multisystem toxicities (OR, 8.1; P=.005). The IR-tox team provided a new multidisciplinary forum to assist providers in diagnosing and managing complex irAEs. This model identifies educational and service needs, and patients with irAEs for whom multidisciplinary care is most sought. CONCLUSIONS: A virtual multidisciplinary toxicity team for irAEs was a feasible and used service, and facilitated toxicity identification and management.

Immune-related adverse events with immune checkpoint inhibitors affecting the skeleton: a seminal case series.

BACKGROUND: The use of immune checkpoint inhibitors is increasing in cancer therapy today. It is critical that treatment teams become familiar with the organ systems potentially impacted by immune-related adverse events associated with these drugs. Here, we report adverse skeletal effects of immunotherapy, a phenomenon not previously described. CASE PRESENTATIONS: In this retrospective case series, clinical, laboratory and imaging data were obtained in patients referred to endocrinology or rheumatology with new fractures (n = 3) or resorptive bone lesions (n = 3) that developed while on agents targeting PD-1, CTLA-4 or both. The average age of patients was 59.3 (SD 8.6), and five were male. Cancer types included melanoma, renal cell carcinoma and non-small cell lung cancer. All fracture patients had vertebral compression, and two of the three had multiple fracture sites involved. Sites of resorptive lesions included the shoulder, hand and clavicle. Biochemically, elevated or high-normal markers of bone resorption were seen in five of the six patients. Erythrocyte sedimentation rate was elevated in three of the four patients where checked. CONCLUSIONS: This case series represents the first description of potential skeletal adverse effects related to immune checkpoint inhibitors. These findings are important for providers caring for patients who experience musculoskeletal symptoms and may merit additional evaluation.

Diabetic serum from older women increases adipogenic differentiation in mesenchymal stem cells.

BACKGROUND: Paradoxically, elderly persons with type 2 diabetes mellitus (T2DM) fracture despite having higher bone density than nondiabetics. Systemic factors associated with aging and T2DM may have detrimental, local effects on the skeleton. One such factor could be by altering the microenvironment of the mesenchymal stem cells (MSCs), multipotent progenitors capable of differentiating into adipocytes or osteoblasts. METHODS: Sera were obtained from four participant groups (n = 40 total, 10 per group): (1) young women with normal glucose tolerance (NGTY), (2) postmenopausal women with NGT), (3) postmenopausal women with impaired glucose tolerance (IGT), and (4) postmenopausal women with T2DM. Sera were incubated with human MSCs for 14 days. Cell proliferation and apoptosis were measured using EdU and TUNEL labeling assays, respectively. MSC differentiation for each group was determined using osteogenic and adipogenic gene expression markers quantified by qRT-PCR, as well as Alizarin Red and Oil Red O staining. RESULTS: Expression of adipogenic genes was greater than twofold higher (P < 0.05) in MSCs cultured with T2DM sera compared to those incubated with NGTY, NGT, or IGT sera. The increase in adipogenic gene expression corresponded with increased Oil Red O staining. Despite the increased adipogenic differentiation of MSCs exposed to T2DM sera, cell proliferation and apoptosis rates as well as osteoblastic activity were not significantly different among the four conditions. CONCLUSIONS: Systemic, circulating factors in the serum of older women with T2DM may promote MSC differentiation into adipocytes versus osteoblasts. Increased differentiation of MSCs into adipocytes is one possible mechanism by which T2DM increases fracture risk.

Potassium citrate supplementation results in sustained improvement in calcium balance in older men and women.

The dietary acid load created by the typical Western diet may adversely impact the skeleton by disrupting calcium metabolism. Whether neutralizing dietary acid with alkaline potassium salts results in sustained improvements in calcium balance remains controversial. In this randomized, double-blind, placebo-controlled study, 52 men and women (mean age 65.2 ± 6.2 years) were randomly assigned to potassium citrate 60 mmol/d, 90 mmol/d, or placebo daily with measurements of bone turnover markers, net acid excretion, and calcium metabolism, including intestinal fractional calcium absorption and calcium balance, obtained at baseline and at 6 months. At 6 months, net acid excretion was significantly lower in both treatment groups compared to placebo and it was negative, meaning subjects' dietary acid was completely neutralized (-11.3 mmol/d on 60 mmol/d; -29.5 mmol/d on 90 mmol/d, p < 0.001 compared to placebo). At 6 months, 24-hour urine calcium was significantly reduced in persons taking potassium citrate 60 mmol/d (-46 ± 15.9 mg/d) and 90 mmol/d (-59 ± 31.6 mg/d) compared with placebo (p < 0.01). Fractional calcium absorption was not changed by potassium citrate supplementation. Net calcium balance was significantly improved in participants taking potassium citrate 90 mmol/d compared to placebo (142 ± 80 mg/d on 90 mmol/d versus -80 ± 54 mg/d on placebo; p = 0.02). Calcium balance was also improved on potassium citrate 60 mmol/d, but this did not reach statistical significance (p = 0.18). Serum C-telopeptide decreased significantly in both potassium citrate groups compared to placebo (-34.6 ± 39.1 ng/L on 90 mmol/d, p = 0.05; -71.6 ± 40.7 ng/L on 60 mmol/d, p = 0.02) whereas bone-specific alkaline phosphatase did not change. Intact parathyroid hormone was significantly decreased in the 90 mmol/d group (p = 0.01). Readily available, safe, and easily administered in an oral form, potassium citrate has the potential to improve skeletal health. Longer-term trials with definitive outcomes such as bone density and fracture are needed.

Type 2 diabetes and bone fractures.

PURPOSE OF REVIEW: To discuss current literature and hypotheses pertaining to the pathophysiology of increased bone fragility and fracture in men and women with type 2 diabetes mellitus. RECENT FINDINGS: Despite high bone mineral density, studies have shown that men and women with type 2 diabetes mellitus (T2DM) are at increased risk for fracture. Complications of T2DM including retinopathy and autonomic dysfunction may contribute to bone fracture by increasing fall risk. Nephropathy may lead to renal osteodystrophy. Lean mass and potentially fat mass, may additionally contribute to skeletal health in diabetes. There is increasing acknowledgement that the marrow microenvironment is critical to efficient bone remodeling. Medications including thiazolidinediones and selective serotonin reuptake inhibitors may also impair bone remodeling by acting on mesenchymal stem cell differentiation and osteoblastogenesis. T2DM is associated with significant alterations in systemic inflammation, advanced glycation end-product accumulation and reactive oxygen species generation. These systemic changes may also directly and adversely impact the remodeling cycle and lead to bone fragility in T2DM, though more research is needed. SUMMARY: Fracture is a devastating event with dismal health consequences. Identifying the extrinsic and intrinsic biochemical causes of bone fracture in T2DM will speed the discovery of effective strategies for fracture prevention and treatment in this at-risk population.