Cathepsin Z, the blood test we have been waiting for osteoporosis

Osteoporosis is a highly prevalent illness, especially among postmenopausal women. Left untreated, it can lead to fragility and compression fractures; in turn, associated with increased mortality and morbidity. Diagnosis of osteoporosis is currently made by bone density scan (DEXA) or when the patient experiences symptoms (fragility or compression fractures).

This scientific report published in Nature is of great significance as for the first-time its authors identify a potential blood test to diagnose osteoporosis – without having patients undergo bone scanning or present with symptoms. The test is Cathepsin Z mRNA and is measured in human peripheral blood mononuclear cells. Cathepsin Z is a protease synthesized by both bone remodeling cells – osteoclast and osteoblasts.

The test is not influenced by acute or chronic inflammation. Its diagnostic positive predictive value (PPV) is 95% with a negative predictive value (NPV) of 80%. Authors found a strong correlation of elevated levels of Cathepsin Z mRNA in patients with osteopenia in addition to those with osteoporosis.

Although study findings need to be fully validated, the results are exciting. Early diagnosis and treatment of osteoporosis are crucial to preventing fractures and its complications.


Bisphosphonate infusion for osteopenia

A group of 2,000 women with osteopenia receiving either zoledronate infusion or placebo were followed for 6 years. Zoledronate 5 mg or placebo was provided every 1.5 years. At the end of the study, the intravenous bisphosphonate reduced vertebral and nonvertebral fractions significantly by about 55% and 35% respectively.

Findings are of major significance as bisphosphonates in general and zoledronate specifically have been approved only for osteoporosis and not osteopenia. Would this expand indications for zoledronate? Should patients with osteopenia be treated?


New FDA Approval: romosozumab for osteoporosis

Romosozumab , brand name Evenity, has now been approved by the FDA as a viable option for patients with advanced osteoporosis.

Romosozumab is a monoclonal antibody that specifically inhibits sclerostin. The approval comes with a major black box warning as the sclerostin inhibitor elevates the risk of heart attack, stroke and cardiovascular deaths.

Prior to Evenity initiation, patients need to be screened carefully for background cardiovascular disease. As the prevalence of both CVD and osteoporosis increases with age, the most likely candidates for such a therapy would be those at the highest risk for fragility or compression fractures.


From diabetes to hyponatremia to osteoporosis

Patients with diabetes mellitus are at increased risk for bone fragility fracture secondary to multiple mechanisms.

Hyperglycemia can induce true dilutional hyponatremia. Hyponatremia is associated with gait instability, osteoporosis, and increased falls and bone fractures, and studies suggest that compromised bone quality with hyponatremia may be independent of plasma osmolality.

Analyses of this research support the hypothesis that hyponatremia is an additional risk factor for osteoporosis and fragility fracture among patients with diabetes mellitus.


More troubles for Prolia

The FREEDOM study shows that vertebral fracture risk goes up once prolia is discontinued. This is consistent with prior case reports on the subject. Adults with previous vertebral fractures are at the highest risk. Authors advise that if prolia is stopped, high-risk patients should be switched to other antiresorptive agents. Bisphosphonates are a natural option given their long half-life.


Phosphorous balance in chronic kidney disease

In the setting of chronic kidney disease, elevated blood phosphorous levels can increase the risk of death, in addition to cardiovascular, parathyroid and bone disorders. This case shows us that the other extreme is also dangerous: severe oral phosphorous restriction and severe hypophosphatemia lead to profound muscle weakness, ostemalacia, osteoporosis and multiple bone fractures. Arisotle’s aurea mediocritas applies nicely here too.


New FDA approval: the first drug for x-linked hypophosphatemia

Crysvita or burosumab is the first drug to be approved by FDA for treatment of x-linked hypophosphatemia in adults and children older than one year of age. It is inherited, rare and unresponsive to vitamin D supplementation. It is a form of ricket and osteomalacia leading to low blood phosphorus levels.  Clinical manifestations are disabled bone growth and development in children and impaired bone mineralization in adults.


Mineral bone disorder in the setting of kidney disease.

This is a nice summary of the latest guidelines on diagnosis and management of mineral bone disease induced by chronic kidney disease. Kidney anomaly can be classified functionally via estimated GFR or structurally via proteinuria.

Guidelines emphasize the need for bone density scan, bone biopsy, parathyroid hormone, calcium and phosphorus measures in the right context. Vitamin D analogs and phosphate binders are also discussed. See below for detailed recommendations.


“Identify first, then intervene” paradigm is confirmed for hip fractures

Despite effective assessment methods and medications targeting osteoporosis and related fractures, screening for fracture risk is not currently advocated in the UK. Study tested whether a community-based screening intervention could reduce fractures in older women.

Results showed that systematic, community-based screening programme of fracture risk in older women in the UK is feasible, and could be effective in reducing hip fractures.


New osteoporosis drug (romosozumab) performs better than fosamax

Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption. In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone.


How to treat diabetes in the context of osteoporosis

This is a nice review of literature on how to approach diabetes management in the setting of osteoporosis. Metformin, DPP4-inhibitors and GLP1-agonists are preferred medications. Insulin and sulfonylurea can cause hypoglycemia leading to confusion, falls, and eventually fractures.  Pioglitazone and invokana can directly contribute to worsening of osteoporosis. The effects of jardiance and farxiga on the bone are less clear. Insulin is recommended for hospitalized patients as they are monitored closely. On the other hand, osteoporosis treatment should not be swayed by diabetes status or management.