“Double drug hope for brittle bone sufferers”, reports the Daily Mail.
This headline follows a small but well-designed trial of treatments for postmenopausal osteoporosis. As women go through the menopause, levels of the hormone oestrogen begin to fall. This drop in oestrogen can lead to a thinning and weakening of the bones, increasing the risk of broken bones (fractures).
While current treatments can help prevent further weakening of the bones, they are not particularly effective at restoring bone strength – known as bone mineral density (BMD). In this study, researchers found that using a combination of teriparatide (Forsteo) and denosumab (Prolia) led to a significant improvement in BMD, when compared to using either medicine on its own.
While this research is encouraging, there are still questions that need answering. For instance, it isn’t clear whether this combination treatment is effective at preventing fractures (more participants would be required) or safe past 12 months (the length of this study).
Similarly, the research was mainly in white, city-dwelling postmenopausal women, so the effectiveness may differ in women from different places and ethnic backgrounds. Similarly, it is not clear whether it would benefit men with osteoporosis (which is less common, but still accounts for roughly 20% of cases).
Aside from these limitations, this research is a positive step forward in the search for new treatment options for osteoporosis. The encouraging results are likely to lead to further, larger studies.
Where did the story come from?
The study was carried out by researchers from at the Massachusetts General Hospital, Boston (US) and was funded by the National Center for Research Resources as well as the pharmaceutical manufactures Amgen and Eli Lilly.
Amgen manufactures denosumab and Eli Lilly manufactures teriparatide.
However, the publication states that the funders of the study had no role in study design, data collection, data analysis, data interpretation, or the writing of the report.
The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
The study was published in the peer-reviewed medical journal The Lancet.
The media reporting generally described the research findings accurately although discussion about the limitations of the research was minimal.
What kind of research was this?
This research used a randomised control trial (RCT) to test whether combining two approved osteoporosis medicines (teriparatide and denosumab) would improve bone mineral density in postmenopausal women.
Osteoporosis is a condition that affects the bones, causing them to become weak and fragile and more likely to break (fracture). These fractures most commonly occur in the spine, wrist and hips, but can affect other bones such as the arm or pelvis. Approximately 3 million people in the UK are thought to have osteoporosis. Although commonly associated with postmenopausal women, osteoporosis can also affect men, younger women and children.
The two drugs, teriparatide and denosumab, are already used individually to treat osteoporosis but they work in slightly different ways. So the researchers wanted to test whether there was any added benefit of using the two drugs together.
Despite drugs being available for osteoporosis, the researchers’ say no currently approved treatment actually restores normal bone density in most patients with osteoporosis – they merely halt the decline. And options for those with severe osteoporosis are limited; the resulting risk of fracture, aside from affecting people’s quality of life, puts a considerable strain on the NHS. It is estimated that there are around a quarter of a million fractures each year in the UK. This means there is a continual need for new or improved treatments.
An RCT is one of the most reliable ways of testing whether a new drug, or in this case combination of drugs, is effective.
What did the research involve?
Between September 2009 and January 2011 the researchers enrolled 100 postmenopausal women (aged 45 years or older, with at least 36 months since last period) with osteoporosis who were at high risk of bone fracture. Women were enrolled through a mailing advertisement and on referral to Massachusetts General Hospital in Boston (US).
Bone mineral density is measured by ‘T-score’ and is simply the number of units, known as standard deviations, above or below the expected average for a healthy 30-year-old adult of the same sex and ethnicity as the patient. Only about 2.5% of women would have a T-score less than -2.0, for example.
The researchers defined high fracture risk as either:
- T-score –2.5 or less at the spine, hip, or femoral neck
- T-score –2.0 or less with at least one risk factor; fracture after age 50 years, parental hip fracture after age 50 years, previous overactive thyroid, inability to get up from a chair with arms raised, or current smoking
- T-score –1.0 or less already with history of a fracture from osteoporosis
Women were split into three equal groups to receive 20 microgram teriparatide daily, or 60 milligram denosumab every six months, or both.
Bone mineral density was measured at 0, 3, 6, and 12 months. This included measuring bone density at the lumbar spine, hip bone and neck of the femur using low-dose x-rays and bone biomarkers. Calcium intake (which can influence bone strength) was also recorded at the start of the study through a food frequency questionnaire.
Women who completed at least one study visit after baseline were assessed in a modified intention-to-treat analysis. Physicians interpreting bone mineral density assessments and the laboratory staff doing bone-marker assays were unaware of patients’ treatment groups.
The analysis compared changes in bone density from baseline (the start of the study) to the different time points (3, 6, and 12 months) for each of the different locations (spine, hip bone, and neck of femur).
What were the basic results?
Of the 100 eligible women, 94 completed the 12 month study. At 12 months, the main findings were that:
- Lumbar spine bone density had increased significantly more in the combination group (9.1%, standard deviation (SD) 3.9) than in the teriparatide (6.2%, SD 4.6) or denosumab (5.5%, SD 3.3) groups.
- Femoral-neck bone density also increased more in the combination group (4.2%, SD 3.0) than in the teriparatide (0.8%, SD 4.1) and denosumab (2.1%, SD 3.8) groups.
- Total hip bone density also increased more in the combination group (4.9%, SD 2.9; teriparatide, 0.7% SD 2.7; denosumab 2.5%, SD 2.6).
All these results were statistically significant.
How did the researchers interpret the results?
The researchers concluded that, “combined teriparatide and denosumab increased bone mineral density more than either agent alone and more than has been reported with approved therapies.” Furthermore, “combination treatment might, therefore, be useful to treat patients at high risk of fracture.”
This small but well-conducted RCT showed that combining licensed osteoporosis medicines teriparatide and denosumab may increase bone density more than either medicine used on their own, in postmenopausal women at high risk of bone fracture.
The researchers highlighted that their results were not consistent with previous trials looking at combination therapies for osteoporosis, which found no benefit of combining them.
However, previous research did not use the same combination of medicines in the same dose as the present trial. It could be the case that the dosages used in previous research were not given at the optimal level.
And while the study showed statistically significant differences in bone density at 12 months, this does not necessarily mean the treatment lead to a reduced rate of fractures – which is the ultimate aim of treating osteoporosis. Larger, longer-term studies are required to see what impact this combination treatment has on fracture risk, as well as assessing how safe and effective both drugs are in the longer-term.
This is particularly relevant because teriparatide is only licensed to be used for a maximum of 24 months (a point the Daily Mail usefully highlighted). It remains to be seen what would happen when this combination of therapies were stopped – would the benefits be reversed, and would it be safe to continue using the medicine longer than recommended?
These issues would need to be thoroughly addressed before this potentially useful combination could feasibly be routinely used in the NHS.