New Horizons: Translational Aspects of Osteomorphs.

Osteomorphs are a newly described osteoclast lineage cell in mice, which are suggested to play a significant role in the maintenance of bone resorption. Preclinical investigations revealed that osteomorphs are generated through the fission of multinucleated bone-resorbing osteoclasts and can also re-fuse with existing osteoclasts. Modifications to RANKL signaling have been shown to alter cycles of fission and re-fusion of osteomorphs in mice. These novel findings were also shown to contribute to the rebound phenomenon after cessation of anti-RANKL therapy in mice. Moreover, the absence of osteomorph-specific genes in mice exhibits bone structural and quality phenotypes. Given these insights, it could be speculated that osteomorphs play a significant role in bone homeostasis, bone metabolic diseases, and response to therapeutics. In this review, we discuss these potential translational roles for osteomorphs. Importantly, we highlight the need for future preclinical and clinical studies to verify the presence of osteomorphs in humans and explore further the translational implications of this discovery.

Origin of Osteoclasts: Osteoclast Precursor Cells.

Osteoclasts are multinucleated bone-resorbing cells and a key player in bone remodeling for health and disease. Since the discovery of osteoclasts in 1873, the structure and function of osteoclasts and the molecular and cellular mechanisms of osteoclastogenesis have been extensively studied. Moreover, it has been well established that osteoclasts are differentiated in vitro from myeloid cells such as bone marrow macrophages or monocytes. The concept showing that osteoclasts are derived from a specific population (named osteoclast precursor cells [OCPs]) among myeloid cells has been long hypothesized. However, the specific precursor population of osteoclasts is not clearly defined yet. A growing body of work provides evidence of the developmental origin and lifespan of murine osteoclasts, particularly in vivo. Here, we review the emerging evidence that supports the existence of OCPs and discuss current insights into their identity.

Epidural Steroid Injections Acutely Suppress Bone Formation Markers in Postmenopausal Women.

CONTEXT: Over 9 million epidural steroid injections (ESIs) are performed annually in the United States. Although these injections effectively treat lumbar radicular pain, they may have adverse consequences, including bone loss. OBJECTIVE: To investigate acute changes in bone turnover following ESI. We focused on postmenopausal women, who may be at greatest risk for adverse skeletal consequences due to the combined effects of ESIs with aging and estrogen deficiency. METHODS: Single-center prospective observational study. Postmenopausal women undergoing lumbar ESIs and controls with no steroid exposure were included. Outcomes were serum cortisol, markers of bone formation, osteocalcin, and procollagen type-1 N-terminal propeptide (P1NP), and bone resorption by C-telopeptide (CTX) measured at baseline, 1, 4, 12, 26, and 52 weeks after ESIs. RESULTS: Among ESI-treated women, serum cortisol declined by ~50% 1 week after injection. Bone formation markers significantly decreased 1 week following ESIs: osteocalcin by 21% and P1NP by 22%. Both markers remained suppressed at 4 and 12 weeks, but returned to baseline levels by 26 weeks. There was no significant change in bone resorption measured by CTX. Among controls, there were no significant changes in cortisol or bone turnover markers. CONCLUSION: These results provide evidence of an early and substantial reduction in bone formation markers following ESIs. This effect persisted for over 12 weeks, suggesting that ESIs may have lasting skeletal consequences. Given the large population of older adults who receive ESIs, further investigation into the long-term skeletal sequelae of these injections is warranted.

Unmasking Fracture Risk in Type 2 Diabetes: The Association of Longitudinal Glycemic Hemoglobin Level and Medications.

CONTEXT: Fracture risk is underestimated in people with type 2 diabetes (T2D). OBJECTIVE: To investigate the longitudinal relationship of glycated hemoglobin (HbA1c) and common medications on fracture risk in people with T2D. METHODS: This retrospective population-based cohort study was conducted using de-identified claims and electronic health record data obtained from the OptumLabs Data Warehouse for the period January 1, 2007, to September 30, 2015. For each individual, the study was conducted within a 2-year HbA1c observation period and a 2-year fracture follow-up period. A cohort of 157 439 individuals with T2D [age ≥ 55 years with mean HbA1c value ≥ 6%] were selected from 4 018 250 US Medicare Advantage/Commercial enrollees with a T2D diagnosis. All fractures and fragility fractures were measured. RESULTS: With covariates adjusted, poor glycemic control in T2D individuals was associated with an 29% increase of all fracture risk, compared with T2D individuals who had adequate glycemic control (HR: 1.29; 95% CI, 1.22-1.36). Treatment with metformin (HR: 0.88; 95% CI, 0.85-0.92) and DPP4 inhibitors (HR: 0.93; 95% CI, 0.88-0.98) was associated with a reduced all fracture risk, while insulin (HR: 1.26; 95% CI, 1.21-1.32), thiazolidinediones (HR: 1.23; 95% CI, 1.18-1.29), and meglitinides (HR: 1.12; 95% CI, 1.00-1.26) were associated with an increased all fracture risk (All P value < 0.05). Bisphosphonates were associated similarly with increased fracture risk in the T2D and nondiabetic groups. CONCLUSION: Longitudinal 2-year HbA1c is independently associated with elevated all fracture risk in T2D individuals during a 2-year follow-up period. Metformin and DPP4 inhibitors can be used for management of T2D fracture risk.

Effect of Abaloparatide vs Alendronate on Fracture Risk Reduction in Postmenopausal Women With Osteoporosis.

CONTEXT: The ACTIVE study demonstrated the antifracture efficacy of abaloparatide in postmenopausal women with osteoporosis. ACTIVExtend demonstrated sustained fracture risk reduction with alendronate in abaloparatide-treated participants from ACTIVE. A direct comparison of the efficacy of abaloparatide and antiresorptive therapies has not been performed. OBJECTIVE: The objective of this analysis is to compare the antifracture efficacy of abaloparatide in ACTIVE with that of alendronate in ACTIVExtend. DESIGN: In this post hoc analysis, the rate of new vertebral fractures for women in ACTIVExtend (N = 1139) was calculated based on baseline and endpoint radiographs for placebo or abaloparatide in ACTIVE and alendronate in ACTIVExtend. Vertebral fracture rates between abaloparatide and alendronate were compared in a Poisson regression model. Fracture rates for nonvertebral and clinical fractures were compared based on a Poisson model during 18 months of abaloparatide or placebo treatment in ACTIVE and 18 months of alendronate treatment in ACTIVExtend. RESULTS: The vertebral fracture rate was lower during abaloparatide treatment in ACTIVE (0.47 fractures/100 patient-years) than alendronate treatment in ACTIVExtend (1.66 fractures/100 patient-years) (relative risk reduction 71%; P = .027). Although the comparisons did not meet statistical significance, after switching from placebo (ACTIVE) to alendronate (ACTIVExtend), the rate of new vertebral fractures decreased from 2.49 to 1.66 fractures per 100 patient-years, and after switching from abaloparatide to alendronate from 0.47 to 0.19 fractures per 100 patient-years. The rates of nonvertebral fractures and clinical fractures were not significantly different. CONCLUSION: Initial treatment with abaloparatide may result in greater vertebral fracture reduction compared with alendronate in postmenopausal women with osteoporosis.

Lower Spine Volumetric Bone Density in Patients With a History of Epidural Steroid Injections.

Context: Epidural steroid injections (ESIs) are a common, effective treatment of lumbar radiculopathy and sciatica. Although the negative skeletal effects of oral glucocorticoids are well established, little is known about the impact of ESI on bone quality. Objective: To investigate the relationship between ESI exposure and volumetric bone mineral density (vBMD) at the lumbar spine (LS) using central quantitative CT. Design: Retrospective study. Setting: University hospital outpatient facility. Patients: All patients had CT scans of the LS between 2011 and 2016. Cases received at least three ESIs prior to the date of CT (n = 121). Controls were matched for age and sex (n = 121). Main Outcome Measures: Cumulative ESI dose was calculated. vBMD was measured at T12 through L5 using QCT Pro phantomless software (MindWays). Results: Mean age of subjects was 65 ± 14 years, and 49% were women. Median number of ESIs was 4 (range: 3 to 16). Median cumulative ESI dosage was 340 mg of triamcinolone or equivalent (range: 150 to 1400 mg). Compared with controls, ESI subjects had lower vBMD at each vertebral level. Higher cumulative dose was associated with lower mean vBMD at T12 to L5 (r = -0.22, P = 0.02). Conclusions: Greater cumulative ESI dose was related to lower vBMD at the LS. To our knowledge, this is the first study to measure vBMD in patients treated with ESIs. Prospective studies are needed to confirm these findings and to help identify the best strategies for preventing bone loss in this population.

Bone Mineral Density Response from Teriparatide in Patients with Osteoporosis.

BACKGROUND: A review of data from large clinical trials reported more than 90% of subjects significantly improved their bone mineral density (BMD) at the lumbar spine (LS) with teriparatide (TPTD) (bone 39:1268-1275, 1). However, our clinical experience suggests that many patients may be non-responders, raising questions as to the true efficacy of TPTD in improving BMD in osteoporotic patients. QUESTIONS/PURPOSES: The purpose of the study is to determine the rate of improvement in BMD following 18-24 months of teriparatide (TPTD) in patients with osteoporosis within an orthopedic hospital setting. METHODS: This is a retrospective chart review of patients with osteoporosis who completed 18-24 months of TPTD therapy. The primary endpoint was the change in BMD at lumbar spine (LS) and hip-femoral neck (FN) and total hip (TH) following treatment. Secondary endpoints included the effect of prior bisphosphonate therapy, age, body mass index (BMI) and family history of fracture on BMD response, and the changes in bone-specific markers during active treatment. RESULTS: Seventy-eight women and men with mean T-scores at the LS = -2.63 met the inclusion criteria. The overall group showed a 10.7% increase in LS-BMD after 24 months of TPTD. Eighty-three percent were considered responders defined as ≥3.0% increase in LS-BMD. Non-responders (16.7%) had mean LS-BMD change = -1.41%. No difference in baseline vitamin D, calcium, creatinine, BMI, age, gender, prior fracture history, or bisphosphonate use was observed between responders and non-responders. No consistent pattern of change in measures of bone markers was noted between responders and non-responders. CONCLUSION: Eighty-three percent of patients with osteoporosis showed a >3% increase in BMD after TPTD treatment. Baseline parameters, prior bisphosphonate therapy, and the changes in bone markers showed no correlation with final BMD outcome.

POTASSIUM CITRATE DECREASES BONE RESORPTION IN POSTMENOPAUSAL WOMEN WITH OSTEOPENIA: A RANDOMIZED, DOUBLE-BLIND CLINICAL TRIAL.

OBJECTIVE: Diets rich in animal protein, such as the typical American diet, are thought to create a high acid load. An association between acid load and bone loss has led to the idea that providing positive alkaline salt therapy could have beneficial effects on bone metabolism. The objective of this study was to investigate the effects of potassium citrate (K-citrate), 40 mEq daily, over 1 year on bone resorption and formation. METHODS: A randomized, double-blind, placebo-controlled trial of 83 women with postmenopausal osteopenia. Levels of bone turnover markers, specifically urinary N-telopeptide of collagen type 1 (u-NTX), amino-terminal propeptide of type 1 procollagen (P1NP), bone-specific alkaline phosphatase (BSAP), and osteocalcin (OC) were compared. Changes in bone mineral density (BMD) were also examined. RESULTS: K-citrate decreased both u-NTX (P = .005) and serum P1NP (P<.001) starting at month 1 and continuing through month 12. No significant change was seen in BSAP or OC. No significant change was seen in lumbar or hip BMD between the 2 groups. CONCLUSION: In women with postmenopausal osteopenia, treatment with K-citrate for 1 year resulted in a significant decrease in markers of turnover. The effect on markers of bone formation was not consistent. K-citrate may serve as a potential treatment for bone loss that is well tolerated and without any significant known long-term consequences.

Management of postmenopausal osteoporosis.

A hallmark of menopause, which follows the decline in the ovarian production of estrogen, is the aggressive and persistent loss of bone mineral and structural elements leading to loss of bone strength and increased fracture risk. This review focuses on newer methods of diagnosing osteoporosis and assessing fracture risk, as well as on novel management strategies for prevention and treatment. Fracture-risk prediction has been significantly enhanced by the development of methods such as the trabecular bone score, which helps assess bone microarchitecture and adds value to standard bone densitometry, and the Fracture Risk Assessment Tool (FRAX) algorithm techniques. The treatment of osteoporosis, which has the goals of fracture prevention and risk reduction, is moving beyond traditional monotherapies with antiresorptives and anabolic agents into new combination regimens.

Insights on accelerated skeletal repair in Cushing's disease.

Cushing's disease with prolonged exposure to high circulating levels of glucocorticoids is associated with deterioration of the structural integrity of bone, resulting in increased skeletal fragility and fractures. The mechanism of bone repair following successful surgical treatment is poorly understood. A 34-year-old man presented with a tibial fracture and severely low BMD, elevated AM serum cortisol, ACTH, and 24 h urinary free cortisol, which did not suppress with 2 days of high dose dexamethasone. Following transphenoidal resection of a pituitary microadenoma, serum cortisol and ACTH normalized. A repeat DXA at 8 months post-resection showed no change in BMD, however the Trabecular Bone Score (TBS), which reported severe deterioration of trabecular bone architecture at diagnosis, improved to normal. At that time, teriparatide (TPTD) was given for 2 years, which resulted in a 53.9% increase in BMD with only a small improvement in TBS. In this patient, spontaneous recovery of trabecular bone architecture was reflected by the early correction in TBS. Subsequent TPTD treatment was associated with marked improvement in BMD, presumably due to enhanced mineralization. Complete skeletal repair was achieved by this two-step mechanism in a very short time following successful surgical treatment for Cushing's disease.

Engaging basic scientists in translational research: identifying opportunities, overcoming obstacles.

This report is based on the Federation of American Societies for Experimental Biology's symposium, "Engaging basic Scientists in Translational Research: Identifying Opportunities, Overcoming Obstacles," held in Chevy Chase, MD, March 24-25, 2011. Meeting participants examined the benefits of engaging basic scientists in translational research, the challenges to their participation in translational research, and the roles that research institutions, funding organizations, professional societies, and scientific publishers can play to address these challenges.

Increased PTH and 1.25(OH)(2)D levels associated with increased markers of bone turnover following bariatric surgery.

The objective of this study was to characterize changes in metabolic bone parameters following bariatric surgery. Seventy-three obese adult patients who underwent either gastric banding (GB), Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion with duodenal switch (BPD/DS) were followed prospectively for 18 months postoperatively. Changes in the calcium-vitamin D axis (25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH)(2)D), calcium, parathyroid hormone (PTH)), markers of bone formation (osteocalcin, bone-specific alkaline phosphatase) and resorption (urinary N-telopeptide (NTx)), as well as bone mineral density (BMD) were assessed at 3-month intervals during this time period. Bariatric surgery resulted in significant and progressive weight loss over 18 months. With supplementation, 25OHD levels increased 65.3% (P < 0.0001) by 3 months, but leveled off and decreased <30 ng/ml by 18 months. PTH initially decreased 21.4% (P = 0.01) at 3 months, but later approached presurgery levels. 1,25(OH)(2)D increased significantly starting at month 12 (50.3% increase from baseline, P = 0.008), and was positively associated with PTH (r = 0.82, P = 0.0001). When stratified by surgery type, median PTH and 1,25(OH)(2)D levels were higher following combined restrictive and malabsorptive operations (RYGB and BPD/DS) compared to GB. Bone formation/resorption markers were increased by 3 months (P < 0.05) and remained elevated through 18 months. Radial BMD decreased 3.5% by month 18, but this change was not significant (P = 0.23). Our findings show that after transient improvement, preoperative vitamin D insufficiency and secondary hyperparathyroidism persisted following surgery despite supplementation. Postoperative secondary hyperparathyroidism was associated with increased 1,25(OH)(2)D levels and increased bone turnover markers.

Pins and plaster aren't enough: a call for the evaluation and treatment of patients with osteoporotic fractures.

A history of an osteoporotic fracture is a powerful predictor of future fractures. Older patients who sustain low trauma fractures are candidates for interventions that should include confirmation of the diagnosis of osteoporosis, adequate calcium and vitamin D administration, and use of an osteoporosis therapy that is proven to lower fracture risk. Recently, however, several reports in the literature have indicated that, in general, those physicians who diagnose and treat fractures, i.e. radiologists, orthopedic surgeons, physiatrists, and those who provide general medical care to these fracture patients, the primary care physicians, are not evaluating patients with acute fractures for the presence of osteoporosis and are not prescribing calcium, vitamin D, or specific pharmacological therapy to reduce future fracture risk. These reports suggest that implementation of a standard of care for the subsequent medical management of the older patient with an acute fracture is needed urgently. Diagnostic tools and several effective therapies exist, but these are underused by the physicians who interface with these patients. A call to action is necessary to reduce the human and economic costs associated with this serious and treatable disease.

The effects of gallium nitrate on bone resorption.

Gallium nitrate has been shown to be an effective treatment for patients with cancer-related hypercalcemia. Clinical studies have also suggested the drug may have considerably broader use in other diseases associated with accelerated bone loss including multiple myeloma, bone metastases, Paget's disease, and osteoporosis. The actions of gallium nitrate on bone are quite distinct from those of bisphosphonates. Preclinical studies show that gallium preferentially accumulates in trace amounts in metabolically active regions of bone. When present, gallium favorably alters the mineral properties to enhance hydroxyapatite crystallization and reduce mineral solubility. The drug also acts on the cellular components of bone to reduce bone resorption by decreasing acid secretion by osteoclasts. This effect appears to be mediated by inhibition of the ATPase-dependent proton pump of the osteoclast's ruffled membrane. Gallium does not inhibit the development or recruitment of osteoclasts to bone tissue, unlike many bisphosphonates that may induce osteoclast apoptosis. Together, these pharmacologic actions may yield a skeletal system with increased calcium and phosphate content and improved biomechanical strength. Gallium nitrate has potent antiresorptive effects on bone that can be achieved at considerably lower doses than are currently used for cancer-related hypercalcemia. Parenteral and oral formulations of gallium appear to have high activity in bone resorptive disorders, and thus development should be vigorously pursued in these diseases.

Gallium nitrate accelerates partial thickness wound repair and alters keratinocyte integrin expression to favor a motile phenotype.

The nitrate form of the Group III transitional element gallium (GN) increases expression of specific structural components of the provisional wound matrix (i.e., collagen type I, fibronectin) in human dermal fibroblasts. To evaluate the potential of GN as a therapeutic option in management of cutaneous trauma, GN-treated partial thickness porcine wounds and experimentally "injured" human keratinocyte (NHK) monolayer cultures were compared with mirror image control (i.e., saline-treated) sites. GN suppressed cell proliferation in both models, as determined by reduced Ki-67 reactivity and significant lengthening of keratinocyte cell cycle transit times, while effectively promoting reepithelialization. The primary effect of GN was apparently to promote cell migration, as neither epidermal thickness nor epidermal differentiation was altered as a result of GN exposure in vivo or in vitro. Significantly enhanced epidermal reepithelialization was associated with alterations in expression of several keratinocyte integrin subunits. GN induced a significant increase in alpha5 expression. alpha5beta1 switching is a characteristic of the motile phenotype in the setting of cutaneous injury. Concomitantly, GN treatment also induced a dramatic (70%) decrease in the expression of the alpha3 subunit; alpha3beta1 binds laminin 5 and is associated with hemidesmosome formation and reestablishment of a nonmotile phenotype. Taken together, the GN-induced changes in integrin expression favor acellular migration. While the molecular mechanism of GN action on resident cells of the skin remains to be defined, these data suggest that GN administration which represses MMP activity in the wound and increases matrix synthesis also accelerates NHK motility and, thereby, may be a useful therapeutic agent for wound repair.