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Continuing professional development

Osteoporosis and its treatment
In this second article of two on osteoporosis, Nuttan Tanna looks at the treatments available for the condition

O
ften, the first sign of low bone mineral
density (BMD) is a non-traumatic frac-
ture. Vertebral fractures can occur after
an ordinary activity, such as lifting a bag, and
even at rest. Early on in the disease, intermit-
tent periods (lasting for days or weeks) of
acute back pain (mild or severe) are inter-
spersed with pain-free periods. After multiple
compression fractures have occurred, how-
ever, a continuous dull, aching pain can
develop in association with spinal deformity.
After the first non-traumatic fracture, the
incidence of vertebral fractures is about one
per year. Multiple fractures, usually of the ver-
tebrae, hip and distal radius can also occur.
Patients with osteoporotic pain are usually
prescribed paracetamol or a non-steroidal Identify knowledge gaps
anti-inflammatory drug, or both. Calcitonin 1. What evidence-based measures can be used
may also be useful after a vertebral fracture if to treat osteoporosis?
other analgesics are ineffective (see below). 2. How do osteoporosis treatments work?
3. What factors affect choice of therapy?
Treatment
Most therapeutic agents currently used to Before reading on, think about how this article may
Dr P Marazzi/SPL

treat osteoporosis inhibit bone resorption. help you to do your job better. The Royal
Two exceptions include teriparatide, which Pharmaceutical Society’s areas of competence for
promotes bone formation, and strontium pharmacists are listed in “Plan and record”,
ranelate, which has a dual mode of action. (available at: www.rpsgb.org/education). This
The aim of anti-resorptive treatment is to Vertebral fractures are article relates to “common disease states”
improve bone repair and increase bone typical in osteoporosis
strength — by inhibiting resorption, there are
smaller cavities for the osteoblasts to fill. modes of action, although further research is
When considering treatment options, it is needed in these areas. Finally, treatment selec-
important to assess the evidence not only on tion should be based on individual circum-
the basis of prevention or reduction of bone stances (see Panel 1). Patient views will impact
loss but also on anti-fracture efficacy. on compliance and should inform prescribing.
Guidelines from the Royal College of Osteoporosis treatments can be categorised
Physicians make recommendations after con- according to their licensed indications. Some
sidering the evidence for efficacy of different agents are only licensed for postmenopausal
interventions in these two categories for osteoporosis and some have a fracture preven-
postmenopausal women (see Table, p583). tion indication.
Selection should also take into account the
long-term effects of agents and the differing Bisphosphonates Three bisphosphonates
are licensed for use in postmenopausal osteo-
porosis and glucocorticoid-induced osteo-
Panel 1: Influences on treatment choice porosis in the UK: cyclical disodium
Factors affecting the osteoporosis treatment chosen include age, sex, disease severity, etidronate with calcium carbonate (Didronel
other co-morbidities and, for women, the presence of menopausal symptoms. For example: PMO), alendronate (Fosamax) and risedronate
sodium (Actonel). In addition, etidronate and
■ For premature menopause, hormone replacement therapy is the first-line choice for alendronate are licensed for osteoporosis in
women up to 50 years old. men. Bisphosphonates decrease osteoclast
■ For symptomatic menopausal women aged (usually between 45 and 55 years), activity and induce osteoclast apoptosis. This
benefits of HRT generally outweigh the risks for use up to five years; but patients can allows more time for secondary mineralisation
choose alternatives for symptom control and use another anti-resorptive treatment so increases the mechanical resistance of bone.
for osteoporosis. The optimum duration of treatment has
■ Raloxifene is best prescribed for asymptomatic postmenopausal women, generally not been established. Alendronate has been
over 55 years, with a risk of vertebral fractures. Raloxifene may be preferred by older used safely for up to 10 years. For risedronate,
women with osteoporosis who cannot tolerate bisphosphonates. data indicate safety with up to seven years of
■ For severe osteoporosis, the suitability of raloxifene, bisphosphonates, teriparatide use. Studies have reported significant reduc-
or strontium ranelate should be considered. tions in both vertebral and non-vertebral
■ Etidronate and alendronate are licensed for use in male osteoporosis but risedronate fracture rate in postmenopausal women with
has been prescribed off-licence for men who experience side effects with alendronate. established osteoporosis following a year’s
■ Bisphosphonates can worsen the symptoms of oesophageal ulcers and this will drive treatment. Cummings et al1 reported that the
the prescribing decision. greatest fracture reduction is achieved in
women with lower BMD.

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 Bisphosphonates do not work optimally
Panel 2: Bone mineral density scanning when there is underlying vitamin D defi-
ciency. This is especially relevant for patients
who may not get enough sun exposure, such
as the elderly and strict vegetarians who do
not eat eggs and who may have underlying
osteomalacia (bone softening due to
poor mineralisaton). Fosavance, a treatment
recently licensed in the UK, offers patients
alendronate combined with vitamin D sup-
plementation in one formulation.
Another recently launched product is

John Greim/SPL
Bonviva (ibandronic acid). This bisphospho-
nate is licensed for the treatment of post-
menopausal osteoporosis and patients need
only take one tablet (150mg) every month.
The definition of osteoporosis highlights low bone mass as an important component of The main adverse effects of ibandronate in
fracture risk. Other skeletal abnormalities and non-skeletal factors, such as falls, should clinical trials were similar to other bisphos-
also be considered. Currently, however, only bone mineral density (BMD) can be measured phonates and included dyspepsia, diarrhoea,
with precision and accuracy and this forms the basis for diagnosis. Current consensus is myalgia, arthralgia and non-specific rash.
that the measurement of BMD of the hip using a dual energy X-ray absorptiometry (DEXA)
scanner is the gold standard. With daily quality control and appropriately trained Postmenopausal osteoporosis The link
technologists the DEXA equipment should deliver a precision of about 1 per cent at the between oestrogen levels and bone density
spine and 2 per cent at the hip. To monitor changes of BMD with time and treatment, was discussed previously (PJ, 22 October,
spinal values are more useful but these can be artificially raised in patients with pp521–4). Treatments licensed for post-
osteoarthritis or other degenerative changes. BMD is presented as g/cm2. A DEXA report menopausal osteoporosis include calcitriol,
will typically provide BMD values as T scores and Z scores for the spine, femoral neck and calcitonin, raloxifene, strontium ranelate and
total hip. BMD T scores can vary according to the site and method of measurement so teriparatide. Their evidence base for fracture
reference standards have been published for the different measurement sites. The prevention is presented in the Table.
prediction of fracture risk is usually based on BMD measurements at the femoral neck. In
general the fracture risk doubles for each standard deviation fall in BMD. Calcitriol Calcitriol (1,25-dihydroxychole-
calciferol) is available in capsules (Rocaltrol).
T and Z scores A T score is the number of standard deviations that separate the patient The recommended dose for postmenopausal
from the mean value for 25-year-old women. The T score value, therefore, classifies osteoporosis is 0.25ng twice daily. Generally,
severity of osteoporosis. The World Health Organization defines T scores as follows: treatment is initiated on specialist recommen-
dation. Plasma calcium concentrations and
■ –1 or higher is normal creatinine levels need to be monitored.
■ Between –1 to –2.5 indicates osteopenia (a decrease in bone density but no increase Calcitriol has been shown to decrease bone
in fracture risk) loss in women with osteoporosis, but study
■ Lower than –2.5 indicates osteoporosis results differ. A decrease in vertebral fracture
■ Lower than –2.5 plus a fragility fracture indicates severe osteoporosis frequency has been demonstrated but no pro-
tective effect has been shown for hip fracture.
The T and Z scores are based on data obtained from caucasian women, but consensus
is that these cut off SD scores can be generally applied to male populations as well. The Z Calcitonin Calcitonin is a hormone that tran-
score is the number of standard deviations which separate the patient from an age- and siently inhibits osteoclast activity without de-
sex-matched healthy caucasian population. creasing osteoblast collagen synthesis. Usually
BMD measurements are recommended in the following situations and where initiated in a consultant clinic, it is available as
assessment will influence initiation of treatment and management: a nasal spray and in a formulation for subcu-
taneous or intramuscular injection. With the
■ Radiographic evidence of osteoporosis or vertebral deformity or both recommended dose of 100 units daily, pa-
■ Loss of height, thoracic kyphosis (after radiographic confirmation of vertebral tients are also prescribed 600mg calcium and
deformity) 400IU of vitamin D. Calcitonin (Miacalic)
■ Previous fragility fracture prevents bone loss in a dose dependent man-
■ Prolonged corticosteroid therapy (eg, oral prednisolone daily for three months or ner. Calcitonin has analgesic properties, offer-
more) ing pain relief when used for up to three
■ Premature menopause (ie, below 45 years of age) months in patients with acute pain following
■ Prolonged secondary amenorrhoea (>1 year) crush fracture (collapsed vertebrae).
■ Primary hypogonadism
■ Chronic disorders associated with osteoporosis (eg, hyperparathyroidism) Raloxifene Raloxifene (Evista) is a novel se-
■ Family history of hip fracture lective oestrogen receptor modulator (SERM)
■ Low body mass index (<19kg/m2) with agonist effects in bone, but antagonist ef-
fects in the breasts and uterus. Although the
Other screening methods Other measures of BMD include peripheral DEXA scanning and term “SERM” was introduced following in-
quantitative ultrasound. The National Osteoporosis Society has published position creased understanding of the tissue-specific
statements for guidance on the various scanning methods and these can be accessed at: action of raloxifene, tamoxifen was the first
www.nos.org.uk/healthprof_info.asp#pub. Bone biochemistry tests include checking SERM to be discovered. During pre-clinical
levels of calcium, corrected calcium, albumin and alkaline phosphate (osteoblasts are development it was noted that raloxifene
alkaline phosphatase rich). Vitamin D and PTH measurements are ordered when further lacked some of the agonist properties demon-
investigation is warranted. strated by tamoxifen and this led to the idea
that different agonist-antagonist properties

582 The Pharmaceutical Journal (Vol 275) 5 November 2005 www.pjonline.com

 Continuing professional development
could be developed for use especially, in this
Table: Assessment of evidence for efficacy of different interventions*

Adapted from Royal College of Physicians Clinical guidelines for prevention and treatment, 2001.
case, in breast and endometrial tissues.
Raloxifene has been shown to slow the Intervention Effect on the prevention or Anti-fracture efficacy in
rate of bone loss. It increases bone density by reduction of postmenopausal postmenopausal osteoporotic
0.5 to 1.0 per cent — less than that achieved bone loss women
with oestrogen. The recommended dose is Spine Non-vertebral Hip
one tablet (60mg) daily. Use is associated with
a small increase in the frequency of hot Alendronate A A A A
flushes, leg cramps, peripheral oedema and Calcitonin A A B B
thrombosis risk. Calcitriol A A A –
Calcium A A B B
Raloxifene has some favourable effects on
Calcium and vitamin D A – A A
biochemical markers of cardiovascular risk. Cyclic etidronate A A B B
Both raloxifene and HRT appear to reduce Hip protectors – – – A
low density lipoprotein cholesterol. Hormone replacement therapy A A A A
Raloxifene has little effect on high density Physical exercise A – B B
lipoprotein (HDL) cholesterol but with HRT Raloxifene A A – –
(combined oestrogen and progestogen), a 10 Reduced alcohol consumption C – – –
per cent increase in HDL cholesterol has been Risedronate A A A A
reported. Raloxifene does not appear to affect Smoking cessation B – – –
triglyceride levels, but oral HRT increases the Tibolone A – – –
Vitamin D – – B B
triglyceride level by 15 to 20 per cent.
The rate of breast cancer in those treated
with raloxifene in the Multiple Outcomes of * Grade A:meta-analysis of randomised controlled trials or from at least one RCT or evidence from at least one well-designed
Raloxifene Evaluation trial was significantly controlled study without randomisation. Grade B: evidence from at least one other type of well-designed quasi-experimental
lower than in those treated with placebo. study or from well-designed non-experimental descriptive studies (eg, comparative studies, correlation studies, case-control
There was a greater reduction in the risk of studies). Grade C: evidence from expert committee reports or clinical experience of authorities
oestrogen receptor-positive cancer with no containing foods and tablets within two hours
significant reduction in the risk of oestrogen of taking the strontium ranelate is important
receptor negative breast cancers. CORE to avoid drug interactions and loss of efficacy.
(continued outcomes for raloxifene evalua- In clinical trials there was no evidence of an
tion) trials suggest that raloxifene could be increased incidence of upper gastrointestinal
used safely for up to eight years. Further clin- side effects and the main side effect of diar-
ical trial data are needed to determine long- rhoea is reported to be short-lived. An
term breast cancer safety with raloxifene. increased risk for thrombosis has been noted
Raloxifene has been shown to increase the with strontium ranelate and this is being
risk of venous thromboembolism to the same investigated by the manufacturers.
degree as oestrogen. One advantage of ralox-
ifene is its antagonistic action in the Teriparatide Teriparatide (Forsteo), a recombi-
endometrium. When taken over two years, nant human parathyroid hormone, promotes
raloxifene did not affect endometrial depth. bone growth. It is the first licensed anabolic
drug used to reduce the risk of vertebral
Strontium ranelate With a dual action (reduc- fractures in established osteoporosis. This
ing bone resorption and increasing bone for- injectable treatment (similar to an insulin pen)
mation), strontium ranelate (Protelos) is the is prescribed and supervised by consultants
first of a new class of osteoporosis treatments. and is supported by “home care” that includes
A randomised controlled trial of strontium training and telephone support.The treatment
ranelate in 1,649 postmenopausal women dose of 20µg daily is currently limited to 18
with osteoporosis, and at least one vertebral months’ use, costing around £5,200.
fracture, reported increases in BMD of 12.7 Teriparatide is contraindicated in those with a
per cent in the lumbar spine and 8.6 per cent baseline risk of osteosarcoma, such as those
in the hip, with a 41 per cent reduction in the with Paget’s disease. Use of an anti-resorptive
incidence of new vertebral fractures after drug either before or with teriparatide may
three years’ treatment.2 In another study, reduce its anabolic skeletal effects.
strontium ranelate reduced the incidence of Treatment with teriparatide over 21
non-vertebral fractures by 16 per cent in Nuttan Tanna, PhD, months in 1,637 postmenopausal women with
5,091 women with osteoporosis. Sub-group MRPharmS, is a specialist osteoporosis and a mean age of 69 years
analysis of 1,977 women aged over 74 years pharmacist who runs reported increased BMD by 9 to 13 per cent
with a T score below –3.0 (see Panel 2), menopause and more than placebo. New vertebral fractures
showed that the risk of hip fracture was osteoporosis medication were reduced by 65 per cent and non-
reduced by 36 per cent.3 It is important to management clinics at the vertebral fractures by 53 per cent.4 Recent
note that nearly 50 per cent of the increase in North West London guidance on secondary prevention of osteo-
BMD relates to skeletal incorporation of Hospitals NHS Trust and is porosis fragility fractures from the National
strontium and this can be misleading in terms a member of the National Institute for Health and Clinical Excellence
of bone density scan reports, results of which Institute for Healthcare and identifies the groups of patients for whom this
are calculated using calcium. Clinical Excellence treatment is suitable, for example, patients over
Strontium ranelate is available as a daily osteoporosis guidelines 75 years old who have had four vertebral frac-
dose of 2g. A sachet of granules is mixed in development group. Dr tures and no improvement in BMD after
water and taken at bed-time, at least two Tanna is also a senior bisphosphonate treatment. However it would
hours after eating, to ensure optimal absorp- visiting lecturer at the not be suitable for patients who do not like
tion from the bowel. Avoidance of calcium- University of Bath having daily injections.

www.pjonline.com 5 November 2005 The Pharmaceutical Journal (Vol 275) 583

 Prophylaxis the large overlap in bone density values of the
The present evidence base for the bisphos- vertebrae and hip in age and sex matched
phonates supports their use to prevent individuals with and without vertebral and
postmenopausal and corticosteroid-induced hip fractures. Intrinsic abnormalities in bone
osteoporosis. Raloxifene is licensed to prevent structure can also contribute because of accu-
postmenopausal osteoporosis. mulation of microdamage, architectural
abnormalities and impaired mineral proper-
Hormone replacement therapy The ties.The co-existence of nutritional osteoma-
menopause is a strong marker for increased lacia in some elderly individuals can further
risk of osteoporosis. The decline in ovarian increase susceptibility to fractures, particularly
function and associated oestrogen deficiency hip fractures.The propensity of the elderly to
results in a number of detrimental effects on fall is an independent risk factor for fractures,
bone, including suppression of osteocyte particularly fractures of the hip and wrist.
survival and impairment of osteoblast response
to mechanical stimuli and repair of ageing Fracture prevention Fractures of the hip
bone. and wrist, the most common fractures in
Many women suffering from menopausal Action: practice elderly patients with osteoporosis, almost
symptoms use HRT and, while on treatment,
will benefit with prevention of further bone
points always result from trauma, usually a fall. In
severe osteoporosis, even a minor fall can
loss. Oestrogens suppress bone remodelling to Reading is only one way to break a femur or wrist. Prevention of injury
the premenopausal level, maintaining the func- undertake CPD and the is, therefore, crucial.
tion of osteoblasts and osteocytes. However, Society will expect to see Tendency to fall is a consequence of age-
with ageing, the risks of HRT can outweigh the various approaches in a ing. Risk increases with decline in vision,
benefits. In addition, HRT would not normally pharmacist’s CPD portfolio. hearing, muscle mass and balance preserving
be used to relieve menopausal symptoms for 1. Osteoporosis is being reflexes, as well as diseases that affect the eld-
more than four or five years but the duration of considered for inclusion erly, drugs that they are treated with and
therapy to prevent osteoporotic fractures needs within the new general environmental hazards (eg, poor lighting) and
to be long. Oral estradiol doses of 1mg and medical services contract, other hazards (eg, alcohol abuse).
above are licensed for osteoporosis protection. within the quality and Strategies for preventing falls and conse-
For the conjugated equine oestrogens the min- outcome framework quent fractures should therefore include:
imum dose for bone protection is 0.3mg daily designed to improve
(Premique Low Dose). Transdermal patch patient care. Audits can be ■ Optimal management of balance-disturb-
systems with estradiol at doses of 50µg or undertaken with practices ing disorders, including visual loss
higher are licensed for osteoporosis prophylaxis. to identify patients on ■ Limitation of patient’s use of balance-
There is ongoing debate about the role of long-term steroids and disturbing drugs, including alcohol
HRT in elderly postmenopausal women, women with premature ■ Regular medication reviews as advocated
especially in those with multiple co- menopause or with a within the National Service Framework
morbidities. More research to identify maxi- family history of hip for Older People
mum duration of therapy is needed. fracture, who might ■ Appropriate education for patients and
benefit from an their carers on the dangers of falling,
Calcium Calcium supplements have been osteoporosis risk including information about periods of
shown to slow bone loss in postmenopausal assessment greatest risk (for example, patients should
women in at least two studies. In one study 2. Medicines use reviews can be warned about rising too quickly after
this effect was maintained when calcium be used to check for good eating or resting and should use a support
supplements were taken for four years. compliance with aid if they tend to experience dizziness)
However in another study with a cohort of osteoporosis treatments ■ Awareness and reduction of home hazards
women who had undergone menopause five and to assess for drugs — increasing home safety includes
or fewer years previously, supplementation did being taken that can cause optimal lighting, elimination of slippery
not affect spinal bone loss. Calcium is less falls. or otherwise hazardous floor surfaces, and
effective than other interventions and there is 3. Work with local practices ensuring adequate hand supports
little convincing evidence that it reduces frac- and PCT committees on
tures. It may be of some benefit, however, if developing osteoporosis
dietary intake is inadequate. Supplements guidelines and link these References
should provide 1g or more of elemental cal- within area-wide patient 1. Cummings SR, Black DM, Thompson DE, Applegate WB,
cium daily, in line with doses used in clinical pathways developed by Barrett-Connor E, Musliner TA, et al. Effect of alendronate on
risk of fracture in women with low bone density but without
trials. local falls services. vertebral fractures: results from the fracture intervention
trial. JAMA 1998;280:2077–82.
Fractures For your work to be presented 2. Meunier PJ, Roux C, Seeman E, Ortolani S, Slosman DO,
Bone loss is the main underlying cause of as CPD, you need to evaluate Delmas PD, et al. The effects of strontium ranelate on the
age-related fractures. In the absence of severe your reading and any other risk of vertebral fracture in women with postmenopausal
trauma, fractures do not occur unless bone activities. Answer the osteoporosis. New England Journal of Medicine
density falls below a threshold of about following questions: 2004;350:459–68.
1.0g/cm2 for both vertebrae and femurs.With What have you learnt? 3. Reginster JY, Seeman E, De Vernejoul MC, Adami S,
further bone loss the incidence of both types How has it added value to your Compston J, Phenekos C, et al. Strontium ranelate reduces
the risk of nonvertebral fractures in postmenopausal women
of fractures increases, and although not so well practice? (Have you applied
with osteoporosis: treatment of peripheral osteoporosis
studied, other age-related fractures probably this learning or had any (TROPOS) study. Journal of Clinical Endocrinology and
exhibit a similar relationship. feedback?) What will you do Metabolism 2005;90:2816–22.
Non age-related fracture pathogenesis is now and how will this be 4. Eriksen EF, Robins DA. Teriparatide: a bone formation
more complex and low bone density is not achieved? treatment for osteoporosis. Drugs Today 2004;
the sole determinant. This is emphasised by 40:935–48.

584 The Pharmaceutical Journal (Vol 275) 5 November 2005 www.pjonline.com