Antonio A. Lazzari

Clinical Meaningfulness of the Changes in Muscle Performance and Physical Function Associated With Testosterone Administration in Older Men With Mobility Limitation

CONTEXT Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trials Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participants perception of change. METHODS Men aged 65 years and older, with mobility limitation, total testosterone 100-350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared. RESULTS Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change. CONCLUSIONS Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair-climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this population.

Osteoporotic fractures and hospitalization risk in chronic spinal cord injury

SummaryOsteoporosis is a well acknowledged complication of spinal cord injury. We report that motor complete spinal cord injury and post-injury alcohol consumption are risk factors for hospitalization for fracture treatment. The clinical assessment did not include osteoporosis diagnosis and treatment considerations, indicating a need for improved clinical protocols.IntroductionTreatment of osteoporotic long bone fractures often results in lengthy hospitalizations for individuals with spinal cord injury. Clinical features and factors that contribute to hospitalization risk have not previously been described.MethodsThree hundred and fifteen veterans ≥ 1 year after spinal cord injury completed a health questionnaire and underwent clinical exam at study entry. Multivariate Cox regression accounting for repeated events was used to assess longitudinal predictors of fracture-related hospitalizations in Veterans Affairs Medical Centers 1996–2003.ResultsOne thousand four hundred and eighty-seven hospital admissions occurred among 315 participants, and 39 hospitalizations (2.6%) were for fracture treatment. Median length of stay was 35 days. Fracture-related complications occurred in 53%. Independent risk factors for admission were motor complete versus motor incomplete spinal cord injury (hazard ratio = 3.73, 95% CI = 1.46–10.50). There was a significant linear trend in risk with greater alcohol consumption after injury. Record review indicated that evaluation for osteoporosis was not obtained during these admissions.ConclusionsAssessed prospectively, hospitalization in Veterans Affairs Medical Centers for low-impact fractures is more common in motor complete spinal cord injury and is associated with greater alcohol use after injury. Osteoporosis diagnosis and treatment considerations were not part of a clinical assessment, indicating the need for improved protocols that might prevent low-impact fractures and related admissions.

Association between sclerostin and bone density in chronic spinal cord injury.

Spinal cord injury (SCI) results in profound bone loss due to muscle paralysis and the inability to ambulate. Sclerostin, a Wnt signaling pathway antagonist produced by osteocytes, is a potent inhibitor of bone formation. Short‐term studies in rodent models have shown increased sclerostin in response to mechanical unloading that is reversed with reloading. These studies suggest that complete spinal cord injury, a condition resulting in mechanical unloading of the paralyzed lower extremities, will be associated with high sclerostin levels. We assessed the relationship between circulating sclerostin and bone density in 39 subjects with chronic SCI and 10 without SCI. We found that greater total limb bone mineral content was significantly associated with greater circulating levels of sclerostin. Sclerostin levels were reduced, not elevated, in subjects with SCI who use a wheelchair compared with those with SCI who walk regularly. Similarly, sclerostin levels were lower in subjects with SCI who use a wheelchair compared with persons without SCI who walk regularly. These findings suggest that circulating sclerostin is a biomarker of osteoporosis severity, not a mediator of ongoing bone loss, in long‐term, chronic paraplegia. This is in contrast to the acute sclerostin‐mediated bone loss shown in animal models of mechanical unloading in which high sclerostin levels suppress bone formation. Because these data indicate important differences in the relationship between mechanical unloading, sclerostin, and bone in chronic SCI compared with short‐term rodent models, it is likely that sclerostin is not a good therapeutic target to treat chronic SCI‐induced osteoporosis.

Spinal Cord Injury-Induced Osteoporosis: Pathogenesis and Emerging Therapies

Spinal cord injury causes rapid, severe osteoporosis with increased fracture risk. Mechanical unloading after paralysis results in increased osteocyte expression of sclerostin, suppressed bone formation, and indirect stimulation of bone resorption. At this time, there are no clinical guidelines to prevent bone loss after SCI, and fractures are common. More research is required to define the pathophysiology and epidemiology of SCI-induced osteoporosis. This review summarizes emerging therapeutics including anti-sclerostin antibodies, mechanical loading of the lower extremity with electrical stimulation, and mechanical stimulation via vibration therapy.

Prevention of bone loss and vertebral fractures in patients with chronic epilepsy—Antiepileptic drug and osteoporosis prevention trial

To evaluate whether use of a bisphosphonate (risedronate) in addition to calcium and vitamin D in male veterans with epilepsy who were taking antiepileptic drugs (AEDs) long term can prevent the loss of bone mass (BMD, bone mineral density) associated with AED use compared to patients who were treated with a placebo plus calcium and vitamin D. As a secondary end point we studied the incidence of new morphometric vertebral and nonvertebral fractures.

Circulating sclerostin is elevated in short-term and reduced in long-term SCI

Spinal cord injury (SCI) causes profound bone loss due to muscle paralysis resulting in the inability to walk. Sclerostin, a Wnt signaling pathway antagonist produced by osteocytes, is a potent inhibitor of bone formation. Short-term studies in rodent models have demonstrated increased sclerostin in response to mechanical unloading that is reversed with reloading. Although sclerostin inhibition has been proposed as a potential therapy for bone loss, it is not known if sclerostin levels vary with duration of SCI in humans. We analyzed circulating sclerostin in 155 men with varying degrees of SCI who were 1 year or more post-injury. We report that sclerostin levels are greatest in subjects with short-term SCI (≤5 years post-injury) and decrease significantly over the first 5 years post-injury. There was no association between sclerostin and injury duration in subjects with long-term SCI (>5 years post-injury). In subjects with long-term SCI, sclerostin levels were positively associated with lower extremity bone density and bone mineral content. These data suggest that sclerostin levels are initially increased after SCI in response to mechanical unloading. This response is time-limited and as bone loss progresses, circulating sclerostin is lowest in subjects with severe osteoporosis. These findings support a dual role for sclerostin after SCI: a therapeutic target in acute SCI, and a biomarker of osteoporosis severity in chronic SCI.

Sclerostin: a candidate biomarker of SCI-induced osteoporosis

SummaryWe assessed several circulating proteins as candidate biomarkers of bone status in men with chronic spinal cord injury. We report that sclerostin is significantly associated with bone mineral content and bone density at all skeletal sites tested. We found no association between bone and any other tested biomarker.IntroductionSpinal cord injury results in severe osteoporosis. To date, no circulating biomarker of spinal cord injury (SCI)-induced osteoporosis has been identified. We recently reported that circulating sclerostin is associated with bone density in chronic SCI. In this study, we assessed several circulating proteins as candidate biomarkers of bone in men with chronic SCI.MethodsWe assessed the relationship between bone mineral content or bone density and the following circulating bone-related proteins: sclerostin, DKK-1, soluble receptor activator of nuclear factor kappa B ligand, osteoprotegerin, osteocalcin, and c-telopeptide in 39 men with chronic SCI and 10 men with no SCI.ResultsAfter adjusting for age, lower sclerostin levels were significantly associated with lower bone mineral content and bone density at all skeletal sites tested (p = 0.0002−0.03). No other circulating protein was associated with bone mineral content or bone mineral density (p = 0.18−0.99).ConclusionThese findings suggest that circulating sclerostin reflects the severity of bone loss and is a candidate biomarker of osteoporosis severity in chronic SCI.

Dual Energy X-Ray Absorptiometry of the Distal Femur May Be More Reliable than the Proximal Tibia in Spinal Cord Injury

OBJECTIVE To evaluate the precision of dual energy x-ray absorptiometry scanning at 2 skeletal sites at the knee (proximal femur and distal tibia) in people with SCI. DESIGN Cross-sectional. SETTING Veterans Affairs Medical Center. PARTICIPANTS Subjects (N=20) with chronic SCI. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Precision as determined by root mean square coefficient of variation (RMS-CV) and root mean square standard deviation (RMS-SD). RESULTS At the distal femur the root RMS-CV was 3.01% and the RMS-SD was 0.025g/cm2. At the proximal tibia the RMS-CV was 5.91% and the RMS-SD was 0.030g/cm2. CONCLUSIONS Precision at the distal femur is greater than at the proximal tibia and we recommend it as the preferred site for the longitudinal assessment of bone mineral density at the knee in chronic SCI.

VA-Based Survey of Osteoporosis Management in Spinal Cord Injury

Although osteoporosis is common following spinal cord injury (SCI), no guidelines exist for its treatment, diagnosis, or prevention. The authors hypothesized that wide variations in diagnosis and treatment practices result from the absence of guidelines. This study sought to characterize the diagnosis and management practices within the VA health care system for osteoporosis following SCI.

Major hepatectomy in patients with synchronous colorectal liver metastases: whether or not a contraindication to simultaneous colorectal and liver resection?

Objective  Synchronous hepatic lesions account for 15–25% of newly diagnosed colorectal cancer and its optimal timing to surgery is not completely defined, but simultaneous colorectal and liver resection is recently gaining acceptance, at least in patients with a right colonic primary and liver metastases that need a minor hepatectomy to be fully resected.