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Dr. Marc Wein: Risks of vertebral fractures linked to rapid cessation of denosumab must be carefully considered

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Marc Wein, M.D., Ph.D

Patients with chronic liver disease experience an increased risk of fragility fractures. Treatment with oral bisphosphonates is generally avoided due to concern for esophagitis, especially in individuals with esophageal varices. While intravenous bisphosphonates can be used, additional treatment options are needed. A retrospective cohort study from Japan analyzed the effects of denosumab treatment in 60 patients with osteoporosis and chronic liver disease. Similar to results in other patient populations, denosumab treatment in patients with chronic liver disease reduced bone turnover markers and increased bone density in the spine and hip. The only complication noted was mild hypocalcemia. Given the small sample size and 12 month study duration, it is difficult to extrapolate from this report about risks of more rare complications such as infections and osteonecrosis of the jaw. These results suggest that denosumab may represent an appealing treatment option for fracture risk reduction in this poorly-studied patient population. Risks of vertebral fractures linked to rapid cessation of denosumab must be carefully considered when starting patients on this agent.

Some young women can present with very low bone density and multiple fragility fractures. While multiple FDA-approved therapies exist for post-menopausal osteoporosis, pre-menopausal osteoporosis remains an “orphan disease.” Previous evidence suggests that bone anabolic agents such as teriparatide may be useful for women with idiopathic pre-menopausal osteoporosis (IOP). In a phase 2 randomized clinical trial from New York and Nebraska , 41 women with IOP and multiple fractures were randomized to receive placebo or teriparatide in a cross-over study design. The primary endpoint was bone density in the spine and hip after 6 months of treatment, which was significantly increased by teriparatide versus placebo. In addition, bone biopsies were obtained for measurement of bone formation rate using quadruple labeling with tetracycline and demeclocycline three months into treatment. As expected, biopsies showed that teriparatide treatment increased bone formation rates using this ‘gold standard’ method. This prospective randomized study adds to a growing body of evidence that teriparatide may be a safe method to boost bone density in women with IOP. Future studies are needed to assess the impact of this therapy on fracture risk in this specific patient population.

Type 2 diabetes and osteoporosis are both major problems in our aging population. While some diabetes medications such as thiazolidinediones clearly increase fracture risk, the effects of newer diabetes medications on bone biology and fracture risk remain incompletely understood. In addition to beneficial effects on glycemic control, SGLT2 inhibitors show promise with improving cardiovascular and renal outcomes, even in patients without diabetes. Some studies have suggested adverse effects of SGLT2 inhibitor monotherapy on bone density and fracture risk. However, the impact of combined therapy with SGLT2 inhibitors and metformin on fracture risk remains to be established. In this meta-analysis of 25 randomized controlled trials involving 19,500 patients, fracture risk was assessed, based on available information, for individuals who received metformin monotherapy or metformin plus SGLT2 inhibitor treatment. In general, combination therapy did not increase fracture risk compared to metformin alone. Only 6 of the 25 RCTs included in the meta-analysis investigated bone density or bone turnover markers. In these 6 studies, no obvious changes in skeletal outcomes were noted when comparing metformin alone versus metformin plus SGLT2 inhibitor therapy. Although these data are somewhat reassuring for the skeletal safety of combination metformin/SGLT2 inhibitor therapy, confidence is limited by relatively short follow-up time and lack of detailed information about fractures in these studies which focused primarily on diabetes-related outcomes. Future prospective studies are needed to specifically address the skeletal impact of this commonly-used combination of diabetes medications.

Marc Wein, M.D., Ph.D
Assistant Professor of Medicine
Massachusetts General Hospital Endocrine Unit, Harvard Medical School

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