An improved understanding of bone loss can help women reduce their risk of fractures as they age.
Lee d'Anjou's hip fracture is typical of the damage that osteoporosis wreaks in older women. She moved from the United States to Canada as a young woman, where she raised five children while working as a freelance editor, but she started having health problems in her 70s — and suffered the occasional fall. One day in September 2013, aged 77, she was hanging laundry in the bathroom of her apartment when she turned, lost her balance and fell. She was unable to get back up.
The fall fractured d'Anjou's thigh bone just below where it connects to the hip. The hip area is one of the places most often affected when a woman with osteoporosis breaks a bone, along with the forearm, the spine and the upper arm. Any of these breaks can put a patient in hospital and cause long-term pain and disability, but hip fractures tend to be particularly catastrophic: up to one-quarter of patients die within a year, about half lose some of their physical function, and many require long-term care.
Sadly, these stories are all too common, especially in women. One in three women over the age of 50 will have a bone fracture related to osteoporosis, compared with one in five men of the same age.
Part of this difference between the sexes can be attributed to women's greater longevity: the longer you live with osteoporosis, the greater the chance of fractures. But women are also more likely to have osteoporosis — and to have more severe osteoporosis — than men of the same age. For a long time, investigators believed that the sole cause of that severity in women was the dramatic loss of oestrogen, a hormone that is known to protect bones. But now they have uncovered another cause, in the form of age-related DNA damage that stops the production of bone cells. This newly recognized process affects men as well, but only women face the double whammy of being affected by both forces.
Researchers are working hard to expand their understanding of osteoporosis and its more devilish effects on women. But although new drug classes are emerging, some of these treatment options have foundered or stalled, and concerns are mounting about some of the established drugs. Fortunately, guidelines are changing to encourage early screening, diagnosis and treatment for people with certain risk factors, so that those at greatest risk can take steps to avoid fractures in the first place.
“We often don't know the disease is there until the fracture occurs.”
Osteoporosis has commonly been described as a 'silent disease' because it lacks obvious signs. “We often don't know the disease is there until the fracture occurs,” says Sri Harsha Tella, an endocrinologist at the US National Institutes of Health (NIH) in Bethesda, Maryland. But researchers are slowly getting better at reading the signs. Each advance has the potential to lessen the impact of osteoporosis and change the story for millions of older women like d'Anjou.
Resorb and repair
Healthy bone is a tightly packed matrix of bone cells, with collagen that provides flexibility and elasticity, and minerals containing calcium and phosphate that produce its strength and rigidity. The thickness of this matrix and its microarchitecture (the size of its pores) provide a good indication of a bone's strength, particularly in trabecular (spongy) bone, which is found inside the bones, especially in the long bones of the arms and legs and in the spine. Trabecular bone makes up about 20% of the skeleton; the rest is cortical bone, a more compact structure found mainly on the outside of the bones. Osteoporosis causes trabecular bone to become more porous and less dense (see 'Pore structure'), which explains why fractures are more common in parts of the skeleton with large amounts of trabecular bone.
Much of the recent progress in understanding the biology of osteoporosis stems from a growing insight into how bones continuously break down and rebuild. “We used to consider bone static, but now we know it's a dynamic organ,” says Carmelinda Ruggiero, a geriatrician at the University of Perugia in Italy.
The bone-remodelling cycle unfolds over several weeks. First, a type of bone cell called an osteoclast breaks down or resorbs the existing bone. Then another type, known as an osteoblast, lays down a new matrix composed mainly of collagen, which then hardens. Osteoblasts can also turn into new bone cells called osteocytes. Whereas osteoclasts and osteoblasts are short-lived cells, osteocytes have a half-life of 25 years. They help to direct osteoclasts to break down old bone and guide the mineralization of the new bone matrix. In healthy individuals, bone resorption is balanced by bone formation, so the bones remain dense and strong.
Several factors affect this remodelling process. For example, muscles interact with bones in two ways, says Ruggiero. During weight-bearing exercise, muscles contract and exert a physical load on the bones, which respond by increasing measurably in mass and density over a period of six months to a year. There is also a recently discovered chemical interaction. Muscle and bone exchange cell signalling molecules called cytokines: osteokines from the bone, and myokines from the muscle. One myokine in particular — a hormone called myostatin — inhibits muscle growth and reduces bone mass and strength. Physical exercise can boost the strength of bones by suppressing myostatin.
Scanning electron micrographs of the L4 vertebral trabecular bone from a 31-year-old man (left) and an 89-year-old woman show the increased porosity that occurs in the bones of older women. The pores weaken the bones and can lead to fractures.
Hormone levels can also influence bone remodelling, says Tella. Oestrogen in particular is essential for maintaining a healthy balance in the levels of the cytokines that affect bone breakdown, ensuring that the process does not outstrip bone formation. Since 2004, research has revealed a previously unknown signalling pathway, called Wnt, which promotes bone formation. This pathway is kept in check by an osteokine called sclerostin. Recent evidence suggests that oestrogen suppresses sclerostin, allowing the Wnt pathway to build bone.
If any of the factors involved in bone remodelling — muscle signals, hormone regulation, bone resorption or bone creation — goes awry, this can unbalance the remodelling cycle and lead to osteoporosis. Osteoporosis can be determined clinically by the T-score, which compares current bone mineral density with that of an average 30-year-old.
For women such as d'Anjou, the unbalancing starts at menopause, with a drastic loss of oestrogen. Bone resorption increases by more than 50%, and women lose on average 1.9% of their bone mineral density per year. Men's bones are also protected by oestrogen — testosterone is converted to oestrogen with the help of an enzyme called aromatase. Men's oestrogen levels decrease as they age, but only slightly.
After menopause, women's bones (and those of men in the same age group) take a separate age-related hit. “If you have a 60-year-old woman and a 75-year-old woman with the same T-score, family history, and body-mass index, the fracture risk in the 75-year-old is much, much higher,” says Tella.
Why ageing affects the bones so much is only just coming to light, thanks to research led by Robert Pignolo, a gerontologist at the Mayo Clinic in Rochester, Minnesota. It is well known that, as we age, more of our cells become senescent — they stop dividing and lose function. Pignolo's team has found that osteocytes are among these senescent cells. In addition, as we get older, more fat cells appear in our bones. It was thought that fat was simply replacing bone cells lost through resorption, but Pignolo found that it comes from a different source. Ageing affects the mesenchymal stem cells that differentiate into either osteoblasts or fat cells. As mesenchymal stem cells in the bones suffer DNA damage during ageing, they are more likely to become fat cells than osteoblasts1. This DNA damage can also cause mesenchymal stem cells to express a protein called p53, which can prevent the stem cells from differentiating into osteoblasts2. The net effect is that ageing reduces the number of osteocytes and osteoblasts, impairing the body's ability to form new bone.
As women pass through menopause, they are affected first by the loss of oestrogen, which increases bone breakdown, and then, as they get older, by difficulty creating new bone. As a result, the bone matrix becomes thinner and contains larger spaces. Bones can then snap at their weakest points with minimal impact.
Industrialized countries have overhauled their guidelines for screening and treating osteoporosis in recent years to focus on prevention through a diet high in calcium, adequate vitamin D from sunshine and food, and weight-bearing exercise. The guidelines urge physicians to screen patients using risk calculators that include factors such as sex, age, body mass index, other illnesses and drug use. Once women have a certain level of risk, or are a certain age, most guidelines recommend testing bone mineral density to determine whether they have osteoporosis and, if they do, to see how advanced it is.
When osteoporosis has been diagnosed, it is important to reduce the chance of falling. Non-slip flooring and wearing padding on the hips can help prevent a fall or fracture, says Suzanne Morin, who studies osteoporosis at the McGill University Health Centre in Montreal, Canada. “If you want to make any headway, you have to tackle all of these aspects,” she adds.
Nevertheless, many cases of osteoporosis will not be diagnosed until the patient breaks a bone. “We hope that their first fracture is not the hip,” says Morin, because this has a high rate of complications and death. Drugs are available, but their use should be carefully considered, says Tella. “Once a patient is on them, they have to be on them for years.”
After surgery, d'Anjou was initially treated with oestrogen-replacement therapy, and then a bisphosphonate drug was added. These are the two mainstays of osteoporosis therapy, but in both cases their use has declined. Oestrogen has been used less, and for shorter periods, since a landmark 2002 study3 by the Women's Health Initiative showed that hormone-replacement therapy with oestrogen plus progestin increased the risk of breast cancer, stroke and blood clots. The use of bisphosphonates has fallen since reports of problems including severe jawbone decay surfaced in 2003 — although this was mainly in people taking high doses of bisphosphonates for cancer4.
However, both studies still found benefits for people with osteoporosis, and Tella thinks that these outweigh the risks. “If we want to avoid one fracture, we need to treat only 10 people with bisphosphonates,” he says, whereas the jaw problem has occurred in only 1 out of about 100,000 patients. Nevertheless, many specialists say that bisphosphonates should be discontinued, at least temporarily (a 'drug holiday'), after five years. This drawback has stimulated the hunt for second- and third-line drugs.
Improved understanding of the biological pathways in bone remodelling led to the development of several new drug classes in the 2000s, but these have come with problems of their own (see 'More treatments, more problems'). In the case of denosumab, the adverse effects are seen only after a patient stops therapy. In recently described cases, measurements of bone density dropped below the baseline level before treatment started, says Tella. He believes that this rebound effect may be caused by the body trying to catch up with the bone-breakdown cycle that denosumab suppressed. One solution, he says, is to switch to bisphosphonates after finishing with denosumab to preserve the gains made in treatment and prevent the subsequent bone breakdown.
But despite these workarounds, Tella stresses that new drugs with better risk profiles are needed. In this regard, there may be some hope. Inhibiting sclerostin allows osteoblasts to increase bone formation. Two monoclonal antibodies to sclerostin — romosozumab and blosozumab — are currently in late-stage clinical testing. Tella says that, until recently, the drugs seemed to be safe for long-term use. However, concern about a slightly higher rate of adverse cardiovascular events for romosozumab over bisphosphonates has recently come to light, leading the US Food and Drug Administration to initially reject the drug.
Another couple of approaches are still on the lab bench, years away from entering clinical trials. One idea is to eliminate the senescent bone cells, which could help with age-related osteoporosis in both sexes, says Pignolo. Research is also under way into a new class of drugs that inhibit myostatin. These anti-myostatin agents have undergone initial testing in humans, but only in muscle-related conditions so far. The paucity of late-stage research leaves a big gap in the drug development pipeline. “As a clinician, I am kind of worried,” says Tella. “I am not seeing any other drugs that are in phase III trials.”
Back on her feet
Aside from drugs, the standard of care has improved the outcomes for many. Over the past 20 years, the length of hospital stays and hospital-based mortality rates have both fallen. Too much bed rest is known to further weaken muscles and bones. “It is important to mobilize patients very early,” says Morin.
Two weeks after surgery, d'Anjou entered rehabilitation at the regional hospital, receiving intensive physiotherapy and occupational therapy. She did exercises and practised walking. Her rehabilitation continued for a few months at a long-term care residence and then, seven months after her fall, d'Anjou moved back into her apartment. Today, she runs errands and buys groceries once a week, with assistance from a caregiver, and uses a walker to prevent another fall. At the annual conference of d'Anjou's professional association in June 2017, there was warm applause when she walked to the podium to present an award named in her honour. More than three-and-a-half years after fracturing her hip, she is happy to be mobile. “I thought I would never really get out again,” she recalls.
In some ways, d'Anjou was lucky. At the time of her fall she was living independently, was fairly active, and had no cognitive problems — all factors that help patients recover well, says Morin. But not everyone is as fortunate. “Mortality has decreased, but not tremendously,” says Morin. Death rates outside hospital in the year after a fracture remain stubbornly high in the growing number of frail, elderly patients with other serious illnesses, she says.
As the population ages, clinicians such as Morin and Tella hope to change these grim statistics. They are banking on a mixture of guidelines, screening, prevention and treatment to save women from having fractures like d'Anjou's.
Singh, L. et al. Bone 85, 29–36 (2016).
Wang H. et al. Aging Cell 11, 704–713 (2012).
Rossouw, J. E. et al. J. Am. Med. Assoc. 288, 321–333 (2002).
Khan, A. Can. Family Physician 54, 1019–1021 (2008).
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