Osteoporosis

1. Osteoporosis

2. Osteoporosis is a progressive skeletal disease that is characterised by low bone mass, skeletal fragility and susceptibility to fracture.

3. Facts and figures • 1 in 3 women and 1 in 12 men in the UK will have osteoporosis over the age of 50 • Every 3 minutes someone has a fracture due to osteoporosis • An estimated 3 million people in the UK suffer from osteoporosis • Each year the numbers of people with osteoporosis include over • 70,000 hip fractures • 50,000 wrist fractures • 40,000 spinal fractures • Osteoporosis costs the NHS and government over £1.7 billion each year, that's £5 million each day!

4. Risk factors • For women: • a lack of oestrogen, caused by • early menopause (before age 45) • early hysterectomy (before the age of 45), particularly when both ovaries are removed (oophorectomy) • missing periods for six months or more (excluding pregnancy) as a result of over-exercising or over-dieting

5. Risk factors • For men: • low levels of the male hormone, testosterone (hypogonadism) • For men and women: • long-term use of high dose corticosteroid tablets (for conditions such as arthritis and asthma) • close family history of osteoporosis (mother or father), particularly if your mother suffered a hip fracture • other medical conditions such as Cushing's syndrome and liver and thyroid problems • malabsorption problems (coeliac disease, Crohn's disease, gastric surgery) • long-term immobility • heavy drinking • smoking

6. Diagnosis • normal x-ray of bone cannot reliably measure bone density but is useful to identify spinal factures, explains back pain, height loss or kyphosis. • A bone density scan, called a dual energy x-ray absorptiometry (DXA) scan, is used to measure the density of bones and compare this to a normal range. This test is currently the most accurate and reliable means of assessing the strength of bones and your risk or fracture.

7. Treatments • For people who have been diagnosed with osteoporosis there are a range of treatments available. The most common treatments include: • Bisphosphonates are non hormonal drugs, which help maintain bone density and reduce fracture rates. • Calcium and vitamin D supplements can be of benefit for older people to reduce the risk of hip fracture. • Hormone replacement therapy (HRT) is oestrogen replacement for women at the menopause, which help maintain bone density and reduce fracture rates for the duration of therapy. • Selective Estrogen Receptor Modulators (SERMs) are drugs which act in a similar way to oestrogen on the bone, helping to maintain bone density and reduce fracture rates specifically at the spine. • Testosterone therapy is testosterone placement for men with low testosterone levels to help maintain bone density.

8. Osteoporosis Defn • The definition of osteoporosis is centred on the level of bone mass, measured as BMD. • For diagnostic purposes, two thresholds of BMD have been defined by the World Health Organization, on the basis of the relationship of fracture risk to BMD. • The first threshold- defines the majority of individuals who will sustain a fracture in the future (osteoporosis), and • The second a higher threshold more appropriate to the prevention of bone loss in women at the time of the menopause (low bone mass or osteopenia). • Osteoporosis’ denotes a value for BMD or bone mineral content that is 2.5 standard deviations (SDs) or more below the young adult mean value (T-score less than –2.5). • ‘Low bone mass’ means a T-score that lies between –1 and –2.5. • ‘Severe’ or ‘established’ osteoporosis denotes osteoporosis as defined above in the presence of one or more documented fragility fractures.

9. Key points • The NOS endorses the Royal College of Physicians’ guidelines, which currently provide the most up-to-date recommendations about treatment for physicians. • The bisphosphonates (alendronate, etidronate and risedronate), • calcium andVitamin D, HRT and raloxifene are the licensed treatments generally prescribedfor the prevention and treatment of osteoporosis, all of which have evidence to support their anti-fracture efficacy. • Several other drugs are also under development. • There is currently no concrete evidence that, as an intervention, exercise reduces the risk of fracture. • Falls prevention strategies, including fitness training and use of hip protectors, may protect against fracture risk in older women. • To date there have been very few studies that have directly compared the antifracture efficacy of the different treatment approaches.

10. Bisphosphonates • There are currently three bisphosphonate drugs licensed for osteoporosis in the UK; • Alendronate (Fosamax), • Cyclical Etidronate (Didronel PMO) • Risedronate (Actonel) • all of which have an anti-resorptive effect on bone. • They are currently available as daily tablets, • Alendronate can also be taken weekly. Pamidronate, which is available as an • infusion, is also prescribed by some consultants (out of licence) for those patients with severe gastric problems.

11. Bisphosphonates • Large randomised controlled trials have shown that alendronate and risedronate reduce the • risk of vertebral fracture by about 50% • the treatments work rapidly, bringing about a reduction in fracture risk within one year. • Other studies have shown that • alendronate and risedronate also reduce the risk of other fractures, including hip fracture. • However, this effect is much less marked in those individuals who do not have low bone density.

12. Calcium and vitamin D • Supplementation with 1200mg of calcium and 800iu of vitamin D has been shown to • significantly reduce the risk of non-vertebral fractures, including hip fracture, in older women living in sheltered accomodation. • There is also evidence that calcium and vitamin D taken in similar doses protects against fractures other than in the spine, in older women living independently.51 • However, it remains uncertain as to whether these benefits are dueto vitamin D, calcium or a combination of both. • Vitamin D deficiency is common amongstthe institutionalised elderly • the question as to whether vitamin D alone protects against hip fracture is currently being examined in multi-centre trials. • There is some new • evidence that it may help to reduce falls by influencing neuromuscular function.

13. Calcium and vitamin D • Except perhaps for frail older people, calcium and vitamin D supplementation is not sufficient to treat individuals with osteoporosis. • Supplementation is required for those who are • housebound, • have restricted exposure to sunlight, or • have an inadequate calcium intake

14. Hormone Replacement Therapy (HRT • HRT is available in many different forms which provide oestrogen, cyclical oestrogen and progestogen or both hormones in a continuous combined product • daily tablets, • patches, • implants, • Gel • nasal spray, • A synthetic steroid, tibolone (Livial) is also available.

15. (WHI) trial • The most recent evidence comes from the Women’s Health Initiative (WHI) trial, which has confirmed that HRT brings about a significant reduction in risk for all clinical fractures • In healthy post-menopausal women. These results should however be interpreted in context, as the trial also demonstrated that HRT was associated with an increased risk of • breast cancer and deep vein thrombosis, • as well as a small but significant increase in the risk of heart disease and stroke. • There is also increasing evidence for loss of the beneficial effects of HRT after treatment is withdrawn.

16. Selective Estrogen Receptor Modulators (SERMs) • Raloxifene(Evista) is the only SERM currently licensed in the UK for the prevention and treatment of vertebral osteoporosis. • The SERMs work like oestrogen in a beneficial way on certain organs of the body (i.e. the skeleton), remain neutral on the endometrium, whilst inhibiting the detrimental effects of oestrogen on the breast.

17. Selective Estrogen Receptor Modulators (SERMs) • A large randomised controlled trial has shown that raloxifene significantly reduces vertebral fractures by 30-50% after one year of treatment. • However, the study was unable to show any significant reduction in non-vertebral fractures, including hip fracture. • Raloxifene has also been demonstrated to reduce breast cancer risk and has favourable effects on heart disease risk.

18. Licensed treatments used less frequently • Both calcitriol and calcitonin are licensed for osteoporosis • are effective in reducing the risk of vertebral and non-vertebral fractures in postmenopausal women. • However, the data is not as conclusive as for the other licensed treatments. • The anabolic steroid nandrolone deconoate (Deca-Durabolin) is also licensed for osteoporosis, although there is currently no clinical evidence that its use reduces the risk of fracture.

19. Treatments currently under development • Parathyroid hormone(teriparatide) has an anabolic effect and works by stimulating bone formation. • There is also evidence that it improves the structure of bone, an effect not seen with anti-resorptive drugs. • Recent studies have demonstrated that teriparatide significantly reduces the incidence of both vertebral and non-vertebral fractures, although there is currently no separate evidence for reduction in hip fracture risk. • The effect of teriparatide on vertebral fractures was particularly marked amongst women with moderate to severe vertebral deformities.

20. Other treatments under development • Include several bisphosphonates (i.e. pamidronate, clodronate, ibandronate and zoledronate) and strontium.

21. Calcium and Vitamin D • In all of the above trials calcium and vitamin D were prescribed in addition to the tested drug. • As such, the efficacy of the trials can only be assumed in women with an adequate intake of these nutrients and cannot be assumed in those with low calcium intakes and/or vitamin D deficiency.

22. Non-drug approaches for preventing fracture • Both clinical trials and observational studies suggest that • load bearing exercise such as weight training and high impact exercise, are the most effective at increasing BMD • although the change is not sustained once the exercise is stopped. • There is currently no concrete evidence that exercise programmes reduce the risk of fracture • but fitness may indirectly protect an individual from fracture by improving mobility and muscle function and reducing the risk of falls. • There is good evidence that falls prevention strategies are effective in reducing falls, although the effects on fracture reduction remain unclear.

23. Non-drug approaches for preventing fracture • Hip protector pants, which include a polypropylene shield that decreases the impact of a fall, have been shown to reduce the risk of fracture by as much as 50%. • They are most appropriate for older, frailer women who need to be wearing them when they fall (concordance problems are evident in the trials).

24. What is it like to take a treatment for osteoporosis? • Key points • Women are able to gain reassurance that a treatment for osteoporosis is working mainly through knowledge that its efficacy has been demonstrated in clinical trials. • The treatments do not make women feel any different in the short term but do reduce the risk of fracture and the possibility of further pain and disability in the future. • Several treatments for osteoporosis are associated with side effects and risks and some involve complicated treatment regimens. As a result, concordance can be problematic. • A woman may need to try several different treatments before she finds one that is both appropriate and tolerable. A choice of treatments is therefore important. • Clear guidance on prescribing and access to a broad range of treatments will help health professionals manage a patient’s condition effectively.

25. Side effects of treatment • In general, problems with calcium and vitamin D are rare, although some women do experience bloating, constipation and an upset stomach. • Teriparatide also appears to be well tolerated in the clinical trials to date, although high doses of the drug were associated with headaches and nausea in some women. • Concordance with HRT can be problematic, as demonstrated in the research studies. • Postmenopausal women taking HRT may return to monthly or irregular bleeds, experience premenstrual symptoms and breast tenderness, and are faced with the difficult decision of considering the potential benefits of the treatment for osteoporosis versus the risk of breast cancer, DVT, stroke and heart disease.

26. Women taking raloxifene may experience troublesome hot flushes. This makes it an inappropriate treatment for younger postmenopausal women who are already coping with menopausal symptoms. • Use of raloxifene is also related to an increase in risk of DVT,similar to that of HRT. • Alendronate and risedronate are unsuitable for those with regular heartburn, stomach ulcers or a hiatus hernia that causes symptoms. • A number of women phoning the NOS helpline have also reported problems with musculoskeletal pain. • Similarly, etidronate can cause nausea and diarrhoea, as well as bloating and constipation due to the calcium carbonate that has to be taken for a period of 76 days following the drug.

27. To reduce any potential difficulties bisphosphonates need to be taken in a very specific way. • The complicated treatment regimens can be restrictive for active women with busy lifestyles and may be off-putting for older women, especially those who are unable to follow instructions. • Some women find it difficult to remain upright after taking the tablets, perhaps because of another chronic condition, and those who need to eat regularly or take other medications can find the fasting times difficult. • Weekly formulations e.g. for alendronate may help to make the regimens more acceptable.

28. Treatment • Key points • Decisions about the treatment of osteoporosis are currently guided by then recommendations of the Royal College of Physicians, which highlight a selective case-finding approach to target treatment in those at highest risk. • Despite this, the NHS is still in need of coherent and authoritative prescribing practices for osteoporosis. • All women should be offered a choice of treatment so that they can find one that is both tolerable and appropriate to their personal needs. • In addition to drug therapy women should also receive advice on how to make other lifestyle changes to reduce the risk of fracture i.e. exercise, dietary habits and smoking, as well as referral to a falls service, if necessary. • The management of osteoporotic fracture should be fully comprehensive and include strategies, such as hydrotherapy, physiotherapy and pain management clinics, to help women cope with pain and disability.

29. Investigations • FBC, ESR • Bone and liver function tests [Ca, P, alk phos, albumin, AST/gGT] • Serum creatinine • Serum TSH • If indicated • Lateral thoracic and lumbar spine X-rays • Serum paraproteins and urine Bence Jones protein • Isotope bone scan • Serum FSH if hormonal status unclear [women] • Serum testosterone, LH and SHBG [men]

30. RCP Algorithm

31. REYKJAVIK, Iceland, Nov 03, 2003 (United Press International via COMTEX • An Icelandic firm has identified a gene linked to osteoporosis, a disease that is responsible for 1 million U.S. bone fractures a year. • Decode Genetics, an Icelandic company trying to identify genes that underlie common human diseases, said the people with any of three specific variants of the gene for osteoporosis have a threefold risk of developing the disease, according to the study published in the journal Public Library of Science.

32. NEW YORK (Reuters Health) - high cholesterol increases the risk of heart disease, but new research from Italy suggests that it may also be bad for the bones. • In a study of postmenopausal women, those with higher levels of the "bad" form of cholesterol were much more likely to show signs of bone thinning than women with normal cholesterol. • The findings do not prove that high cholesterol is to blame for bone thinning, but the results do provide a possible explanation for studies suggesting that cholesterol-lowering drugs called statins protect bones, researchers report in the journal Obstetrics and Gynecology. • Very little is known about how cholesterol levels may affect the risk of developing the brittle-bone disease osteoporosis. Studies that have examined the relationship between levels of LDL cholesterol - the "bad" type of cholesterol - and the risk of bone thinning have produced mixed results. ] • In the new study, a team led by Dr. Andrea Poli at the University of Milan measured bone density and cholesterol levels in 1,303 women ages 45 to 65 who had been through menopause.

33. PTH and Alendronate: Combining Treatments Shows No Bone Density Advantage • Combining the bone-building treatment parathyroid hormone (PTH) with alendronate, a drug that slows bone loss, produces no significant improvement in bone mineral density (BMD) beyond that produced by the individual drugs, according to two new studies involving postmenopausal women and men with low BMD. • The two studies, reported in the September 25 issue of the New England Journal of Medicine and supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), one of the National Institutes of Health, both tested BMD in the spine and hip. BMD, a common indicator of bone health, is used to diagnose the bone-weakening disease osteoporosis, detect low bone mass before the disease develops and help predict the risk of future fractures.

34. DEXA Scan • A DEXA scan report compares the patient's bone mineral density values with those of young normal patient (T score) and • with age matched normal patient (Z score). By comparing a patient's bone density against their peers, a low score indicates there may be a reason other than age related bone loss.

35. Patients risk factors • Patients risk factors for osteoporosis that should play a part in the decision to begin treatment include: • a maternal history of a hip fracture, • any previous fracture after the age of fifty, • tall height at age of 25, • poor health, • some sedatives and anticonvulsant drugs, • and the inability to rise from a chair without the use of the arms.

36. The current treatment recommendations are the start of drug therapy to reduce the risk fracture for all women with a bone mineral density T score of less than -2 without other risk factors and for those with a T score of less than -1.5 if other risk factors are present.