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.

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.

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, 90 mmol 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 six months. At six months, net acid excretion was significantly lower in both treatment groups compared to placebo and negative, meaning subjects’ dietary acid was completely neutralized (−11.3 mmol/day, 60 mmol/day; −29.5 mmol/day, 90 mmol/day, P < 0.001 compared to placebo). At 6-months, 24-hour urine calcium was significantly reduced in persons taking potassium citrate 60 mmol (−46 ± 15.9 mg/day) and 90 mmol (−59 ± 31.6 mg/day) daily 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/day compared to placebo (142 ± 80 mg/day, 90 mmol vs. −80 ± 54 mg/day, placebo; p = 0.02). Calcium balance was also improved on potassium citrate 60 mmol/day, 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, 90 mmol/d, p=0.05; −71.6 ± 40.7 ng/L, 60 mmol/day, p=0.02) while bone specific alkaline phosphatase did not change. Intact parathyroid hormone was significantly decreased in the 90 mmol/day 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.

BackgroundThe 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 presentationsIn 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.ConclusionsThis 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.

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.

Background: Immune checkpoint inhibitors (ICIs) may cause immunerelated 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 immunerelated 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 (n5106; 91%) and suitability to treat with ICIs (n511; 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 5.035) or with multisystem toxicities (OR, 8.1; P 5.005). 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.

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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).