CPG - Management of Osteoporosis (Revised 2015) PDF
CPG - Management of Osteoporosis (Revised 2015) PDF
CPG - Management of Osteoporosis (Revised 2015) PDF
12(GU)
June 2012
Revised 2015
Clinical Guidance
on Management
of
Osteoporosis
2 012
Endorsed by:
Malaysia Health Technology Assessment Section (MaHTAS)
Medical Development Division, Ministry of Health Malaysia
Level 4, Block E1, Precinct 1
Federal Government Administrative Centre
62590, Putrajaya, Malaysia
Copyright
The copyright owner of this publication is the Malaysia Osteoporosis Society
(persatuan Osteoporosis Malaysia). Content may be reproduced in any number of
copies and in any format or medium provided that a copyright acknowledgement to the
Malaysia Osteoporosis Society is included and the content is not changed, not sold,
nor used to promote or endorse any product or service, and not used in an inappropriate
or misleading context.
02
Table of Contents Page
Statement of Intent 06
Preface 07
01. Background 15 - 16
02. Introduction 17 - 19
04. Diagnosis 21 - 28
12. Acknowledgements 50
13. Disclosures 50
14. Appendices 51 - 53
15. References 54 - 63
03
Clinical Guidance on Management of Osteoporosis
Chairperson Co-chairperson
Chan Siew Pheng Yeap Swan Sim
Consultant Endocrinologist Consultant Rheumatologist
Subang Jaya Medical Centre, Subang Jaya Medical Centre,
Subang Jaya, Selangor Subang Jaya, Selangor
Expert Panel
Malik Mumtaz
Consultant Endocrinologist /
Consultant Nuclear Medicine Physician
Island Hospital, Penang
Reviewers
04
Levels of evidence and grades of recommendation
Level of evidence
IIa Evidence obtained from at least one well designed controlled study without
randomisation
Grades of recommendation
Grade Recommendation
B (evidence levels IIa, IIb and III) Requires availability of well conducted
clinical studies but no randomised
clinical trials on the topic of recommendation
05
STATEMENT OF INTENT
This Clinical Guidance is not intended to serve as a standard of medical care. Standards
of medical care are determined on the basis of all clinical data available for an individual
case and are subject to change as scientific knowledge advances and patterns of care
evolve.
The contents of this publication are a guide to clinical practice, based on the best
available evidence at the time of development. Adherence to this guide may not ensure
a successful outcome in every case, nor should they be construed as including all proper
methods of care or excluding other acceptable methods of care. Each physician is
ultimately responsible for the management of his/her unique patient in the light of clinical
data presented by the patient and the diagnostic and treatment options available.
06
PREFACE
Knowledge does not stagnate and therefore practice needs to keep pace. It has
therefore become necessary to update the Clinical Practice Guidelines (CPG) on
Management of Osteoporosis. There has been a greater usage and accessibility of DXA
scanners to measure bone mineral density and thus proper interpretation becomes an
important issue. This allows the early detection of low bone mass but it remains
important to put the place of DXA scanning in perspective. The new recommendation is
to assess and treat fracture risk and not mere numbers so the overall assessment of risk
is essential. There are new anti-resorptive agents available and there is the exciting
prospect of reliably increasing bone by stimulating bone formation. With improved assays
and measurement of bone turnover markers that are more readily available and accurate,
their place in monitoring needs to be addressed.
Once again a multi-disciplinary panel of experts have come together to plough through a
burgeoning literature on osteoporosis and related topics to produce this update. The
panel reviewed the current and most recent literature since the last CPG published in
2006 to update the document, which we have called a Clinical Guidance. It is important
to accept that we cannot be comprehensive in all aspects. Subtle aspects of related
topics such as menopause are addressed elsewhere. We must congratulate the panel
for their tireless effort in the realisation of the CPG update.
We hope the Clinical Guidance will be of use to all practicing medical practitioners.
07
KEY STATEMENTS AND RECOMMENDATIONS
Osteoporosis is defined as a skeletal disorder characterised by compromised bone
strength predisposing a person to an increased risk of fracture. Bone strength reflects
the integration of bone density and bone quality. Bone density (g/cm2 or g/cm3) is
determined by peak bone mass and amount of bone loss. Bone quality refers to
architecture, turnover, damage accumulation, and mineralisation.
(Level IV)
Observational studies suggest that a similar cut-off point to that used in women can be
taken for diagnosis in men.
(Level IV)
The Clinical significance of osteoporosis lies in the resulting fracture. The exact
magnitude in Malaysia is not known but hip fracture incidence in 1996-1997 in the over
50 years of age is 90/100,000 and is likely to increase with our ageing population.
(Level III)
The risk of fracture increases progressively with decreasing BMD. Risk of fractures
increases approximately two fold for each SD decrease in BMD.
(Level Ia)
In those with a low trauma fracture, a BMD measurement, though advisable, is not
necessary before starting therapy.
(Grade C, Level IV)
The gold standard for measuring BMD is dual-energy x-ray absorptiometry (DXA).
DXA still remains the recommended method in the diagnosis of osteoporosis and
monitoring the effect of therapy. Other methods for measuring BMD such as
quantitative computed tomography (QCT) and quantitative ultrasound (QUS) are not
recommended for diagnosing osteoporosis but QUS may help in case-finding.
08
FRAX is a fracture risk assessment tool used to evaluate the 10-year probability of
hip and major osteoporotic fracture risk that integrates clinical risk factors and bone
mineral density at the femoral neck in its calculations. Until more Malaysian data are
available, it is recommended to use the Singapore prediction algorithm.
Exercise A - -
Smoking cessation C - -
Prevention of falls - - B
Estrogen A A A
Raloxifene A A -
Alendronate A A -
Tibolone A A -
09
Table 2. The strength of recommendations concerning interventions in the treatment
ofosteoporosis is shown in the following table:
Alendronate A A A
Risedronate A A A
Zoledronate A A A
Ibandronate A A -
Strontium A A A
Denosumab A A A
Estrogen A A A
Raloxifene A A -
Calcitriol / Alfacalcidol A A C
Calcium (vitamin D) A A B
r-PTH A A -
The recommended daily intake for calcium is 1000mg (both dietary and supplements)
and for vitamin D is 800IU.
(Grade C, Level IV)
The choice of drug for established osteoporosis, especially those with previous
fracture, must be an agent shown not only to increase BMD, but also shown to reduce
fracture both at the spine and hip.
(Grade A, Level Ia)
Hip fractures should be surgically managed promptly to allow early ambulation. Spine
and wrist fractures may need operative intervention.
(Grade C, Level IV)
Patients on prednisolone more than 5mg daily or its equivalent, for more than 3
months, should be assessed for the presence of glucocorticoid-induced osteoporosis
and treated as required.
(Grade C, Level IV)
Secondary causes of osteoporosis should be excluded in men. Bisphosphonates, and
PTH, denosumab and strontium have been shown to be effective, and androgen is
useful in hypogonadal men.
(Grade A, Level Ib)
10
Figure 1
Algorithm for the management of postmenopausal osteoporosis
Clinical assessment
(include OSTA)
General measures:
Calcium intake (B)
Patients with Physical activity (B) Patients with
risk factors but prior low
no fracture In the elderly:
trauma fracture
Vitamin D + calcium (A)
Prevention of falls (B)
OSTEOPOROSIS
(with/without BMD)
Treatment options:
T score: T score: T score: Bisphosphonates (A)
-1 < -1 to > -2.5 -2.5 Denosumab (A)
SERMs (A)
r-PTH (A)
Strontium Ranelate (A)
High Low NORMAL OSTEOPENIA OSTEOPOROSIS Activated Vitamin D (A)
Risk Risk
Monitor If multiple
risk factors
present (C)
The treatment options found in the algorithm for the management of postmenopausal
osteoporosis reflects the order of preference according to current medical evidence. The
level of evidence is not a yardstick for comparing relative efficacy. There are few comparative
studies between therapeutic agents but the therapeutic aim is for clinical fracture reduction
rather than an increase in BMD. Therefore, agents with clinical fracture reduction are ranked
higher in the hierarchy of therapeutic choice than agents with only BMD data.
11
Figure 2
Algorithm for the management of male osteoporosis
Consider checking:
serum testosterone Monitor BMD
bone profile** 1-2 years
full blood count
protein electrophoresis
TSH
ESR
24hr urine calcium
Monitor BMD
Treat underlying 1-2 years
secondary cause with:
Bisphosphonates (A)
Denosumab (A)
r-PTH (A)
Strontium (A)
Monitor BMD
1-2 years * FRAX Score > 20%
12
Approach to postmenopausal women and men age > 50 years initiating or
receiving glucocorticoid therapy 3
General Measures
* for low and medium-risk patients, recommendations are for an anticipated or prevalent
duration of > 3 months of glucocorticoid treatment
* FRAX score
Low Risk (< 10%)
Medium Risk (10%-20%)
High Risk (> 20%)
13
Approach to premenopausal women and men age < 50 years initiating or
receiving glucocorticoid therapy3
General Measures
Prevalent No prevalent
fragility fracture fragility fracture
Glucocorticoids Glucocorticoids
> 3 months 1-3 months
alendronate
if prednisolone No consensus
> 7.5 mg/day
OR
risedronate
if prednisolone
> 7.5 mg/day Glucocorticoids Glucocorticoids
> 3 months 1-3 months
OR
alendronate If prednisolone
teriparatide > 5 mg/day:
if prednisolone OR
alendronate
> 7.5 mg/day risedronate or risedronate
prednisolone OR OR
<7.5 mg daily:
no consensus zoledronic acid If prednisolone
OR > 7.5 mg/day:
zoledronic acid
teriparatide
14
1. BACKGROUND
In 2001, the Malaysian Osteoporosis Society, in collaboration with Ministry of Health and
Academy of Medicine produced the first clinical practice guidelines for the management
of osteoporosis. This was updated in 2006. Since then, the field of osteoporosis has
continued to advance and it is timely for a review and update.
1.1.1 Methodology
The previous Clinical Practice Guidelines published in 2006 was used as the
baseline. To update the document, a systematic review and literature search by the
members of the Working Group, using PubMed (MEDLINE) and The Cochrane
Library, identified all relevant articles on osteoporosis and its assessment, diagnosis
and treatment, from 2005 to 2011. The date 2005 rather than 2006 was chosen so
that all studies published just before and after the last guidelines would be reviewed
and none inadvertently overlooked. The studies were assessed and graded with the
levels of evidence as used by the National Guideline Clearinghouse, Agency for
Healthcare Research and Quality, U.S. Department of Health & Human Services,
USA (Page 4). For each statement, studies with the highest levels of evidence were
used to frame the statements. The grade of recommendation was taken from the
Scottish Intercollegiate Guidelines Network grading system (Page 5).
1.2 Objectives
Aid primary care physicians in deciding when to refer patients with difficult
problems to the relevant specialists
15
1.3 Clinical Questions
This guidance would be useful for all health care professionals who manage
patients with osteoporosis, such as primary care physicians/general practitioners,
gynaecologists, orthopaedic surgeons, rheumatologists and endocrinologists as
well as paramedical personnel such as nurse practitioners, nurse specialists,
dieticians and physiotherapists.
16
2. INTRODUCTION
The WHO working group5 defines osteoporosis in women on the basis of the criteria
shown in Table 3. Bone mineral density (BMD) peaks during the third decade of life and
declines with advancing age. In women, this decline accelerates with menopause for
5 -10 years (Figure 5).
(Level IV)
Normal Bone mineral density (BMD) > 1.0 SD of young adult reference
range (T-score > 1.0)
Osteopenia BMD between -1.0 SD and - 2.5 SD below the young adult mean
(1.0 > T-score > 2.5)
Osteoporosis BMD < - 2.5 SD of the young adult mean (T-score < 2.5)
Severe / BMD < - 2.5 SD of the young adult mean with the presence of 1 or
Established more fragility fractures
Osteoporosis
In men older than 50, osteoporosis may be diagnosed if the T-score of the lumbar
spine, total hip or femoral neck is 2.5 or less.6
17
Figure 5: Bone Loss During Adult Life7
Bone
Density Men
- 20 to 30%
Women
- 35 to 50%
40 60 80 Age (year)
Osteoporosis related fractures have been recognised as a major health problem in the
elderly. Similar to trends in many countries with increasing life expectancy, Malaysia is
expected to have a growing number of elderly individuals. The common sites of fracture
are the spine, wrist and hip. Hip fractures are associated with high morbidity and a
mortality rate of up to 20% in the first year. Majority of those who survive are disabled
and only 25% will resume normal activities.8,9
(Level III)
In 1997, the incidence of hip fracture in Malaysia among individuals above 50 years of
age was 90 per 100,000. There was a marked increase in the incidence among the older
age group. The incidence of hip fracture is consistently higher in women (Table 4).7
18
Table 4: Incidence of Hip Fracture in Malaysia by Age Group 199710
50-54 10 10 10
55-59 20 30 20
60-64 40 50 40
65-69 60 100 80
3
75 320 640 510
In our community, the Chinese had the highest incidence of hip fractures compared
to the Malays and Indians. Chinese women accounted for 44.8% of hip fractures.10
The direct hospitalisation cost for hip fractures in 1997 is estimated at RM 22 million.
This is a gross underestimate of the total economic burden, as it does not take into
account the costs incurred in rehabilitation and long term nursing care. Therefore, in
an ageing population this cost will escalate without appropriate intervention.10
(Level III)
19
3. CLASSIFICATION AND RISK FACTORS
1. Endocrine
Cushings syndrome
Hypogonadism
Thyrotoxicosis
Hyperparathyroidism
2. Drugs
Glucocorticoids
Heparin
Anticonvulsants (phenytoin)
Immunosuppressants
Thiazolidinediones
Oncology (e.g. Aromatase inhibitors, androgen deprivation therapy)
3. Chronic Diseases
Renal impairment
Liver cirrhosis
Malabsorption
Chronic inflammatory polyarthropathies (e.g. rheumatoid arthritis)
4. Others
Nutritional deficiency e.g. anorexia nervosa
Multiple myeloma and malignancy
Osteogenesis imperfecta
Post-gastrectomy / gastric bypass surgical procedures
20
3.3 Risk factors for Osteoporosis:
Osteoporosis is a silent disease without any symptoms in most patients until fractures
have occurred. While population screening is not cost effective, identification of risk
factors will help in case finding.11
(Grade C, Level IV)
Non-modifiable Modifiable
5. Family history of osteoporotic hip 6. Low body weight (BMI < 19kg/m2)
fracture in first degree relative
7. Estrogen deficiency
6. Personal history of fracture as 8. Impaired vision
an adult
9. Recurrent falls
4. DIAGNOSIS
Most patients are asymptomatic and diagnosis is made only after a fracture. Common
clinical presentations include:
21
4.2 Diagnosis
As multiple risk factor assessment does not predict bone mass with sufficient
precision,13 (Grade B, Level IIa) bone mineral density (BMD) remains the mainstay in
decision making to identify the at-risk patient requiring further investigation.
If a BMD measurement is not available, calculating the risk of fractures using Fracture
Risk Assessment Tool (FRAX) can help in deciding treatment strategies.
Fracture Risk Assessment Tool (FRAX) estimates the 10-year probability of hip fracture
and major osteoporotic fracture (hip, clinical spine, proximal humerus, or forearm), for
untreated patients between age 40 to 90 years using clinical risk factors which include
an individual's age, sex, weight, height, prior fracture, parental history of hip fracture,
smoking, long-term use of glucocorticoids, rheumatoid arthritis and alcohol
consumption.14,15
The country-specific FRAX prediction algorithms are available for some countries but
not for Malaysia. For Malaysians, we recommend the use of ethnic specific algorithms
(e.g. Singapore Chinese or Hong Kong Chinese, Singapore Malay, Singapore Indian)
until local data is available.
BMD is not necessary for calculation of fracture probability. However, it improves the
prediction of fracture probability. If a BMD is available, only the femoral neck / total hip
BMD is to be used. BMD input from non-hip sites has not been validated with FRAX and
is therefore not recommended.14
22
The treatment interventions in FRAX have been partly based on cost-effectiveness, for
which there is no Malaysian data. Notwithstanding that, we would propose using the
National Osteoporosis Foundation Clinicians Guide to Prevention and Treatment of
Osteoporosis (2010),16 in that postmenopausal women and men over the age of 50
should be considered for treatment if they had a previous hip or vertebral fracture or a
T-score < -2.5 on DXA after exclusion of secondary causes of osteoporosis. In patients
with osteopenia, initiation of treatment is recommended with a fracture probability of
more than 3% at 10 years for hip or 20% at 10 years for major osteoporosis related
fracture.
If FRAX is not accessible, elderly individuals over 65 years of age with multiple risk factors
who are at sufficiently high risk for osteoporosis, can be started on treatment.17,18
Recommendation
The Singapore prediction algorithm should be used when using the FRAX tool.
Treatment can be started in pafients with osteopema when the 10-year fracture
probability is more than 3% for hip and more than 20% for major osteoporosis-related
fractures.
(Grade C, Level IV)
4.3 Screening
Recommendation
OSTA can be used to screen postmenopausal women for further assessment of
osteoporosis.
(Grade B, Level III)
23
4.4 Investigations
Radiological osteopenia is apparent in plain X-rays only after more than 30% of bone
loss has occurred.
4.5.1 Densitometry
BMD measurement gives an accurate reflection of bone mass and helps in establishing
the diagnosis of osteoporosis (Table 3). It is important to use race-specific reference
ranges when available. BMD results are reported as T-scores (comparison with the
young adult mean) and Z-scores (comparison with the mean of individuals of the same
age) (Figure 6). The risk of fracture is increased two fold for each SD reduction of T-score
in BMD.19
(Grade A, Level Ia)
a) DXA
The gold standard for diagnosis is DXA, which is measured at the hip and lumbar spine.
The procedural standard for performing DXA should be followed to ensure quality and
consistency. Prediction of fracture risk is site-specific. When site-specific measurements
are not available, other skeletal sites can be used to provide an adequate estimation of
fracture risk.
24
Peripheral DXA (phalanges / distal radius / calcaneum) is useful for site-specific fracture
risk prediction. Forearm BMD measurement can be used to predict fracture risk.
However, their predictive capacity for hip fracture appears to be less than that of DXA
of the spine and hip.
The decision to measure BMD should be based on an individuals risk profile and is
indicated if the results will influence management. (See Table 7)
Recommendation
BMD measurement with DXA remains the gold standard for the diagnosis of
osteoporosis. The decision to measure BMD should be based on an individuals
risk profile and is indicated if the results will influence management.
T
Z
0.72
*A +1 SD
-1 SD
Age (year)
25
Table 7: Indications for BMD Measurement*
1. All women aged 65 and above and men aged 70 and above6
2. Presence of strong risk factors
Estrogen deficiency
Premature menopause (< 45 years of age) including surgical menopause
Prolonged secondary amenorrhoea
Hypogonadism
Glucocorticoid therapy (see Section 8.1 on Glucocorticoid-Induced Osteoporosis)
Maternal family history of hip fracture
Low body mass index (<19 kg/m2)
Other conditions associated with osteoporosis
Anorexia nervosa
Malabsorption
Hyperparathyroidism
Hyperthyroidism
Prolonged immobilisation
Cushings syndrome
Post-bariatric surgical bypass
Drugs [e.g. aromatase inhibitors, Gonadotropin-releasing hormone (GnRH)
agonists]
3. Radiological osteopenia and/or vertebral deformity
4. Previous low trauma fractures of hip, spine and/or wrist
5. Loss of height, thoracic kyphosis
6. Low weight for age (OSTA**) for postmenopausal women (Appendix 1)
* BMD should only be measured in postmenopausal women who are willing to consider
available interventions.
** OSTA = Osteoporosis Self-assessment Tool for Asians
b) QCT
26
4.5.2 Quantitative Ultrasound (QUS)
QUS in the diagnosis and monitoring of treatment is not recommended. Problems with
this modality include the diversity of techniques, the lack of standardisation and
comparable local normal ranges. QUS appears to be a good predictor of fracture and
is currently recommended as a screening tool. The decision to treat should not be
based on the results of QUS. The criteria for diagnosis and recommending treatment
based on ultrasound are not well established.23,24,25
(Grade C, Level IV)
Women with low QUS results should be referred for BMD measurement.
Bone turnover markers (BTM) are useful to identify patients at high risk of future
fractures.26,27,28 It can also be used to evaluate treatment efficacy and compliance to
therapy. 28,29,30 They should not be used for the diagnosis of osteoporosis. Changes in
level of BTM can be seen within 3-6 months after initiation of drug therapy.26,27,28
Resorption Formation
Serum C-telopeptide (CTX) N-terminal propeptide of type 1
procollagen (P1NP)
Serum CTX (bone resorption) and P1NP (bone formation) are used in the management
of patients with osteoporosis.29
(Grade B, Level IIa)
27
4.6 Monitoring of Therapy
The aim of monitoring is to assess the response to treatment.
Patients should have regular clinical assessments
Currently, monitoring of treatment using QUS and peripheral DXA is not
recommended
If biochemical markers are available, two separate baseline measurements
of the same marker need tobe carried out followed by one repeat
measurement 2-3 months after initiating therapy and yearly thereafter, if
indicated. These measurements should be taken at the same time of the
day to minimise the effect of diurnal variation.
(Grade C, Level IV)
5.1 Nutrition
Nutrition is important during bone growth as well as aging. In addition to ensuring adequacy
of calcium and vitamin D, a balanced diet throughout life is important for bone health.30
Maintenance of an adequate protein and energy intake is important especially in the elderly.31
Adequate protein intake helps minimize bone loss among patients who have sustained
hip fractures.32,33
(Grade C, Level IV)
In one study, patients with hip fracture who received supplemental protein had shorter
hospital stays and better functional recovery.33
(Grade B, Level IIb])
5.1.1 Calcium
Individuals of all ages should have ana dequate calcium intake to maintain bone health.
The recommended levels of calcium intake for Malaysians of all age groups are shown in Table
9. Attempts should be made to achieve these levels for maximum benefit to bone health.
For women 50 years old or older, the recommended daily calcium intake is 1000 mg.
This represents the total calcium intake (diet plus calcium supplements, if applicable).34
28
Table 9: Suggested Daily Calcium Intake34
6 - 12 months 400 mg
Children 13 500 mg
4-6 600 mg
7-9 700 mg
Men 19 49 800 mg
> 50 years 1000 mg
Women 19 49 800 mg
> 50 years 1000 mg
Pregnantc Third trimester 1000 mg
Lactating 1000 mg
a The absorption of calcium from human breast milk is higher than from baby formula, therefore
the calcium requirement for non breast-fed babies is higher.
c During pregnancy and lactation, calcium absorption is increased and fetal bone mineralisation can be
obtained with no detectable mobilisation of maternal bone for this purpose. However, in
Malaysia where habitual calcium intake is low, a high calcium intake may possibly benefit the
fetus. The recommendation for calcium during pregnancy and lactation is 1000 mg/day.35
For optimal absorption, the amount of calcium should not exceed 500 to 600 mg per
dose, irrespective of the calcium preparation. For patients requiring more than 600 mg
of calcium supplement daily, the dose should be divided.36,37,38
29
Table 10: Studies investigating calcium absorption from different sources38
Calcium lactate 13 32
The risk of cardiovascular events is predominantly observed in studies with higher doses
of calcium supplements (1000-2000 mg) and lower doses are deemed to be safe.
Calcium from dietary sources was not associated with a higher risk of coronary heart
disease.42 Therefore, it is encouraged to have adequate calcium intake from food sources.44
(The calcium content of some common foods is given in Appendix 2)
5.1.2 Vitamin D
Blood levels of 25(OH)D provide the best index of vitamin D stores. It has been suggested
that levels of 25(OH)D of >20 ng/mL (50 nmol/L) is the minimum level required for skeletal
health.45 However, the Endocrine Society recommends a level of 25(OH)D of >30 ng/mL
(>75 nmol/L) for optimal musculoskeletal health.180
For adults 50 years old or older, the Malaysian Recommended Nutrient Intake advocates
400 IU of vitamin D per day, but many experts recommend at least 800 to 1000 IU per day.
Elderly who are institutionalised, immobile, lack outdoor activities and have a poor diet will
benefit from at least 800 IU vitamin D supplementation daily.46
30
Vitamin D supplements are available as ergocalciferol (vitamin D2) and cholecalciferol
(vitamin D3). With daily dosing, vitamin D2 and D3 appear to be equally potent 47
(Level 1a), but with intermittent (weekly or monthly) dosing, vitamin D3 appears to be
about 3 times more potent than vitamin D2 48 (Level IIa)
This suggests that addition of vitamin D did not reduce the elevated risk observed with
calcium supplementation.39
Recommendation
The recommended daily intake for calcium is 1000 mg (both dietary and
supplements) and for vitamin D is 800 IU.
(Grade C, Level IV)
Low body weight and excessive dieting is associated with low bone mineral status and
increased fracture risk 51
(Grade B, Level IIa)
Maintenance of a body mass index of not less than 19 kg/m 2 is recommended for
prevention of osteoporosis.5
(Grade C, Level IV)
5.1.5. Smoking
Cigarette smoking increases osteoporotic fracture risk and thus should be avoided.54
(Grade B, Level IIa)
31
5.1.6. Alcohol intake
Excessive intake of alcohol should be avoided because alcohol has detrimental effects
on fracture risk.55
(Grade B, Level IIa)
5.2 Exercise
Regular physical activity, in particular weight-bearing exercise (e.g. brisk walking, line
dancing) is encouraged in all age groups in order to maximise peak bone mass,
decrease age-related bone loss, maintain muscle strength and balance.56
(Grade C,Level IV)
The individuals health status should be taken into consideration when recommending
an exercise programme.
Poor balance
Reduced muscle strength
Low vitamin D levels
Poor vision
Diseases of nervous & musculoskeletal systems
Excessive alcohol consumption
Certain medications (e.g. sedatives, anti-hypertensives)
Hazards in the home (e.g. steps, inadequate lighting, slippery floors)
Physicians caring for older patients should integrate fall assessment into the history and
physical examination.57
(Grade C, Level IV)
Older persons who present for medical attention because of a fall, report recurrent falls
in the past year, or demonstrate abnormalities of gait and / or balance should have a fall
evaluation performed.58
(Grade C, Level IV)
32
A fall evaluation is defined as an assessment that includes the following: history of fall
circumstances, medications, acute or chronic medical problems, and mobility levels;
an examination of vision, gait and balance, and lower extremity joint function; an
examination of basic neurological function, including mental status, muscle strength,
lower extremity peripheral nerves, proprioception, reflexes, tests of cortical,
extrapyramidal, and cerebellar function; assessment of basic cardiovascular status
including heart rhythm and postural blood pressure.58
33
6. MANAGEMENT OF POSTMENOPAUSAL OSTEOPOROSIS
The treatment interventions in FRAX have been partly based on cost-effectiveness, for
which there is no Malaysian data. Notwithstanding that, we would propose using the
National Osteoporosis Foundations recommended treatment thresholds. We
therefore suggest that postmenopausal women should be considered for treatment, if
they had a previousl ow trauma hip, vertebral or wrist (colles) fracture, or a T-score <
-2.5 on DXA, after exclusion of secondary causes of osteoporosis. In patients with
osteopenia, initiation of treatment is recommended with a fracture probability, based
on the FRAX calculation, of more than 3% at 10 years for hip or 20% at 10 years for
major osteoporosis-related fracture.
(Grade C, Level IV)
Combined oestrogen and progestin appear to increase the risk of breast cancer after
3-5 years, while data on oestrogen only users do not show an increase, up to 7 years of
use. This risk of breast cancer reduces when HT is stopped.73,74,75
(Grade A, Level 1b)
34
The use, dose and duration of use of HT should be individualised and a risk - benefit
assessment carried out annually while on treatment. A full gynaecological assessment is
mandatory prior to starting HT and at regular intervals thereafter. Self breast examination
is advised monthly and clinical breast examination at least annually. A mammogram
should be carried out 1-2 yearly if the initial mammogram is normal.
Absolute contraindications for oestrogen use are undiagnosed vaginal bleeding, severe
liver disease and a history of venous thromboembolism.
(Grade C, Level IV)
HT should be offered to all women with premature ovarian failure in view of the increased
risk of osteoporosis, cardiovascular disease, urogenital atrophy and libido. HT is given till
the normal age of menopause; continuation thereafter is made after a risk-benefit
assessment.76
(Grade C, Level IV)
Recommendations for HT
1. HT can be considered as a first line treatment for prevention and treatment of
osteoporosis in women below 60 years. In this group of women, HT has not
been shown to increase the risk of cardiovascular events, stroke, venous
thromboembolism and haemorrhagic strokes
2. Initiating HT in women after 60 years for the sole purpose of prevention of
osteoporotic fractures is not recommended
3. Combined oestrogen and progestin appear to increase the risk of breast cancer
after 3-5 years, while data on estrogen only users do not show an increase up to
7 years of use
4. The use, dose and duration of HT should be individualized and a risk - benefit
assessment should be carried out annually while on treatment
Tibolone* 2.5 mg
6.2 Tibolone
Tibolone, a selective tissue estrogenic activity regulator (STEAR) is indicated for the relief of
climacteric symptoms and prevention of post-menopausal osteoporosis. In older
post-menopausal women above 60 years, tibolone at 1.25mg increases lumbar spine
BMD by 6.6% and hip BMD by 2.8% with a corresponding decrease in vertebral fractures
by 45% and non-vertebral fractures by 26%. There was a greater reduction in women with
a pre-existent vertebral fracture.78,79
35
In view of an increased risk of stroke, tibolone should not be used in older women (above
60 years) and in women with strong risk factors for stroke.79
(Grade A, Level 1 b)
Raloxifene and estrogen are associated with a similar increased risk of venous
thromboembolism (VTE). However, no cases of VTE were reported amongst healthy
postmenopausal Asian women whilst on raloxifene.85
Other side effects include hot flushes, which are more likely in the peri-menopausal
period, and leg cramps.
(Grade A, Level Ib)
6.4 Bisphosphonates
6.4.1 Alendronate
Alendronate at 10 mg daily for 3 years increases lumbar spine BMD by up to 8.8% and
femoral neck BMD by 5.9% compared to placebo.87 The rate of new vertebral and hip
fracture is reduced by 50% in women with 87 or without 88 prior fracture. Wrist fracture is
reduced by 50% in patients with prior vertebral fracture 89. Fracture reduction is seen
after 1 year of treatment.90
36
Continuous use of alendronate, for up to 10 years, if clinically indicated, produces a
sustained increase in BMD and 55% significant reduction in spine fracture with a good
safety profile.91,92
(Grade A, Level Ia)
6.4.2 Risedronate
Treatment with risedronate 5 mg daily for 3 years increases lumbar spine BMD by 6.4% 93
and femoral neck BMD by 3.4% 94 compared to placebo. This is associated with up to
49% reduction in new vertebral fracture in women with prior vertebral fractures 95 and
39% reduction in non-vertebral fractures.96 Vertebral fracture risk reduction is seen after
6 months of therapy. 97 Reduction of hip fracture risk after 3 years was 40% in women
with confirmed osteoporosis and 60% in women with at least one co-existing vertebral
fracture.94 Currently, the use of risedronate for up to 7 years, is safe and efficacious.98
Risedronate 35 mg once weekly has similar efficacy to the 5 mg daily dosing.97
Treatment with oral ibandronate 150 mg/month increases the lumbar spine BMD by
6.6% over 2 years in postmenopausal osteoporotic women without prior fracture
compared to placebo.99 Oral ibandronate 2.5 mg daily for 3 years reduces vertebral
fracture by 62% in postmenopausal women with prevalent vertebral fracture.100 The
currently licensed ibandronate dose of 150 mg a month has been shown to be
non-inferior to the 2.5 mg daily dose in terms of BMD gain and bone marker
suppression.101 Pooled analysis showed significant reduction of non-vertebral fracture by
38-43% over 2 years.102
(Grade A Level Ib)
6.4.4 Zoledronic acid
Zoledronic acid yearly infusion is also indicated for the prevention of new clinical
fractures in patients who recently (within 90 days) have had a low trauma hip fracture.104
It has also been shown to be associated with a reduction in mortality.104
37
Atypical Femoral Shaft Fractures
The absolute risk of atypical fracture is low, ranging from 1.9-8.4/10,000 patient-years
with average of 5.5/10,000 patient-years.106 The benefits of bisphosphonate therapy, by
reducing classical osteoporotic fracture, outweigh the rare risk of this fracture.105,106
The frequency of ONJ in osteoporotic patients is rare ranging from 0.01 - 0.04% (1 in
2,260 to 8,470)108 patients to <1/100,000109,107 patient years for those on oral (mainly
weekly) bisphosphonates. If extractions were carried out, the calculated frequency is 0.09
- 0.34% (1 in 296 to 1,130 cases).107
However, it is more commonly seen in patients on oncological doses (high dose, IV) of
bisphosphonates, used for treatment of cancer / who have bone metastases, who are
immune suppressed / had radiation / infection / poor oral hygiene / have invasive dental
procedures, where the incidence ranges from 4-13%.110
For patients with upper gastrointestinal disease, risedronate may be better tolerated.111
Intraveneous zoledronic acid is another option.
Patients with CKD stages 1-3 and low T-scores or low trauma fractures, most likely have
osteoporosis rather than renal bone disease. Treatment of osteoporosis does not differ from
usual treatment for postmenopausal osteoporosis. Bisphosphonates can be used safely.
38
CKD Stages 4-5
Bisphosphonates are not recommended for patients with an estimated GFR < 30 ml/min
(See Appendix 4).
When prescribing bisphosphonates for longer than 5 years, evaluation of the need
for continued bisphosphonate therapy is recommended. In patients:
1. with low risk of fracture, consider a drug holiday
2. with evidence of atypical femoral shaft fracture, bisphosphonate therapy
should be discontinued
3. with high risk of fracture, consider continuing bisphosphonate therapy up to
10 years92
Recombinant human PTH 1-34 (r-PTH), teriparatide, is a potent anabolic agent. r-PTH is
indicated for individuals with severe osteoporosis or osteoporosis not responsive to
other anti-osteoporosis therapy.
The drug is contraindicated in patients with open epiphyses (children and adolescents),
Pagets disease of the bone, prior radiation therapy involving the skeleton, bone malignancies,
metabolic bone diseases other than osteoporosis or pre-existing hypercalcaemia.
(Grade C, Level IV)
39
6.6 Strontium Ranelate
Strontium Ranelate reduces bone resorption while promoting bone formation.114
A pooled estimate showed a relative risk reduction of 37% for vertebral fracture114,116 and
14%115,116 for non-vertebral fracture. Efficacy for reduction of incident vertebral fractures
was seen as early as 1 year (49% reduction). In a subgroup of high risk women (i.e. women
aged >74year with a femoral neck BMD T-score <-3.0), the relative risk reduction of hip
fracture was 36% (RR 0.64, 95% CI 0.41-0.99), which was borderline significant. This
anti-fracture efficacy is sustained up to 10 years.117
(Grade A, Level 1b)
Caution is necessary when interpreting BMD change as the increased X-ray absorption of
strontium compared to calcium leads to an amplification of BMD measurement by DXA.
An increase in lumbar spine BMD over a 2 year treatment period is 11.29g/cm2 (CI 10.22
- 12.37) when not adjusted for strontium but is in fact, 5.44g/cm2, (CI 3.41 - 7.46) when
adjusted for strontium content. At the femoral neck over a 2 year period, there is an
increase of 5.73g/cm2 (CI 5.15 - 6.32).118
Side effects include diarrhoea and Drug Rash with Eosinophilia Systemic Symptoms (DRESS).
Based on a recent review by the European Medicines Agency (EMA) in 2014 assessing the
increased signal for non-fatal myocardial infarctions in the clinical trials, they recommended
that strontium is indicated for the treatment of severe/established osteoporosis in
postmenopausal women at high risk of fracture to reduce the risk of vertebral and hip fracture,
and severe/established osteoporosis in men at increased risk of fracture. It should only be
used for whom treatment with other medicinal products approved for the treatment of
osteoporosis is not possible due to, for example, contraindications or intolerance. The
decision to prescribe strontium should be based on an assessment of the individuals patients
overall risk.182
If the patient has any of the criteria below, do not prescribe strontium180 :
Established, current, or past history of ischaemic heart disease, peripheral vascular
disease and/or cerebrovascular disease
Uncontrolled hypertension
Current or previous Venous Thromboembolic Events (VTE), including deep vein
thrombosis and pulmonary embolism
Temporary or permanent immobilization due to e.g. postsurgical recovery or prolonged
bed rest
Hypersensitivity to strontium ranelate or any of its excipients
6.7 Denosumab
Denosumab is a human monoclonal antibody (IgG2) that inhibits the formation,
function and survival of osteoclast by preventing RANK (receptor activator of nuclear
factor kappa-B) ligand from activating its only receptor, RANK, thus reducing bone
resorption.119
40
Over 3 years, denosumab 60mg given 6 monthly subcutaneously, significantly increased
BMD by 9.2% at the lumbar spine, 6.0% at the total hip, 4.8% at the femoral neck and 3.5%
at the distal 1/3 radius, as compared to placebo.120 It significantly reduced the risk of new
vertebral fractures by 68%, hip fractures by 40% and non-vertebral fractures by 20%.120
(Grade A, Level 1b)
6.8 Calcium
In established osteoporosis, calcium supplementation alone is not adequate for fracture
prevention. However, calcium supplementation is necessary for optimal response to other
treatment modalities. (see section 5.1.1)
6.9 Vitamin D
Vitamin D supplementation at 800 IU/day in combination with calcium has been shown to
reduce fracture in elderly populations with vitamin D insufficiency. 50,118
(Level Ib)
In most of the recent osteoporosis trials, active therapies have demonstrated significantly
increased bone density and greater fracture reduction, despite calcium and vitamin D in
the placebo arm. Therefore, calcium with vitamin D alone is generally considered
inadequate for the treatment of osteoporosis, and should usually be prescribed together
with other active osteoporosis therapies.
(Grade C, Level IV)
In a global epidemiological study of postmenopausal women (which included Malaysian
subjects), 61% were found to be vitamin D insufficient (<30 ng/mL).183 Fifty percent of the
Malaysian cohort were vitamin D insufficient. Therefore, we recommend vitamin D
supplementation of 800-2000 IU daily, in osteoporotic women, in addition to other active
osteoporosis treatments.
(Grade C, Level IV)
41
Overall recommendation for the treatment of postmenopausal osteoporosis
The choice of drug for established osteoporosis, especially those with previous
fracture must be an agent shown not only to increase BMD, but also shown to
reduce fracture both at the spine and hip.
(Grade A, Level Ia)
The goals of treatment are early mobilisation and a return to normal activities.
Conservative management of hip fractures is discouraged because it places the patient
at risk of respiratory problems, thromboembolic disease, pressure ulcers and further
bone loss. These patients are best treated by early surgical intervention.128
Symptomatic relief of spinal pain is often difficult to achieve. Morphine and other potent
analgesics may be required. Calcitonin is a useful adjunctive analgesic agent.127
Adequate calcium122, vitamin D6 (Grade A, Level Ib) and protein intake aids fracture
healing.123 (Grade B, Level III) All patients with osteoporotic fractures are at high risk
for the development of further fractures. They should receive active management for
osteoporosis and advised regarding prevention of falls.
(Grade A, Level Ia)
42
Recommendations
8. SECONDARY OSTEOPOROSIS
Bone loss occurs most rapidly in the first 6-12 months of oral glucocorticoid
therapy.124,125
(Level III)
Prednisolone 5 mg daily or its equivalent, for more than 3 months is associated with
osteoporosis.16,133
(Grade B, Level III)
However, higher doses of glucocorticoids for a shorter duration may also carry the
same risk.
(Level IV)
Standard doses of inhaled or topical glucocorticoid use have not been shown to
adversely affect BMD. Inhaled high potency glucocorticoid over an extended period of 7
years have been associated with significant bone loss.134
(Level IIa)
8.1.1 Diagnosis
The use of BMD measurement for the diagnosis of GIOP is not crucial, but may be
useful in the monitoring of therapy. DXA measurement at the hip provides the best
assessment of fracture risk as degenerative changes at the spine may cause falsely
high BMD result.135 Diagnostic thresholds in GIOP have not been established for
peripheral densitometry using either DXA or ultrasound, which therefore should not be
used for assessment or monitoring.135,136
43
The use of FRAX is recommended to categorise patients into low, medium and high risk
groups with respect to the 10-year risk of fracture.
In postmenopausal women and men over 50 years old with low risk of fracture,
treatment is recommended when prednisolone (or its equivalent) > 7.5 mg daily is taken
for more than 3 months. In medium risk patients, treatment is recommended at any dose
of glucocorticoid when taken for more than 3 months. In high risk patients, treatment is
suggested for any dose of glucocorticoid taken for any length of time.
For premenopausal women of non-childbearing potential and men under 50 years old
with a prevalent osteoporotic fracture, treatment is recommended if prednisolone > 5
mg daily is given for > 1 month. For premenopausal women of childbearing potential,
treatment is recommended when prednisolone > 7.5 mg daily is given for > 3 months.3,
179
(See algorithms: Figure 3, page 13 and Figure 4, page 14)
There has been a recommendation that the FRAX risk estimates are adjusted according
to the daily dose of glucocorticoids. For low-dose exposure (< 2.5 mg daily of
prednisolone or equivalent), the probability of a major fracture is decreased by about
20% depending on age. For medium doses (2.5 7.5 mg daily), the unadjusted FRAX
value can be used. For high doses (>7.5 mg daily),probabilities can be upward revised
by about 15%.137
8.1.2 Management
44
Table 13: Grades of Recommendation for Preventive and Therapeutic Interventions
in Glucocorticoid-induced Osteoporosis
Alfacalcidol A A ND 143,144
Calcitriol A ND ND 146
Etidronate A A A 148,149
Pamidronate A A ND 151,152
Risedronate A A A 154,155
Zoledronate A A ND 157
45
In a study comparing alendronate, vitamin D and calcitriol, alendronate increased lumbar
spine BMD by 5.9% over 2 years, compared to 0.5% and 0.7% loss on vitamin D and
calcitriol respectively. There was no difference at the femoral neck.158 In a prevention
study comparing alendronate and alfacalcidol over 18 months, patients on alendronate
maintained or improved their lumbar spine and femoral neck BMD compared to BMD
loss in the alfacalcidol group.159 IV zolendronate produced a better gain in lumbar spine
and femoral neck BMD compared to oral risedronate over 1 year.157 Teriparatide led to a
better gain in lumbar spine and femoral neck BMD compared to alendronate over 3
years.153 Alendronate and risedronate reduced vertebral fractures in patients on
glucocorticoid therapy.141,155
The treatment pathways for postmenopausal women and men over the age of 50 with
GIOP are shown in Figure 3 (page 13). For premenopausal women and men below the
age of 50, the suggested pathway is shown in Figure 4 (page 14).
Table 14: Clinical factors that may shift an individual to a greater risk
category for glucocorticoid-induced osteoporosis
Declining central bone mineral density measurement that exceeds the least
significant change
46
8.2 Renal Osteodystrophy
8.3 Amenorrhoea
Extreme physical activity, anorexia nervosa and hypogonadal disorders in young women
may be associated with low BMD. Bone loss in amenorrhoeic women show the same
pattern as in postmenopausal women. Treatment is with hormone replacement.
8.4 Drugs
47
9. OSTEOPOROSIS IN MEN
Fifty to sixty percent of cases are due to secondary causes such as hypogonadism
(including androgen deprivation therapy), excess alcohol intake, hyperparathyroidism,
intestinal disorders, malignancies, glucocorticoid therapy and immobilisation. For
every one SD reduction in age-matched mean BMD (Z score), fracture risk increases
two-fold.161
(Grade B, Level III)
9.1 Treatment
Once weekly alendronate160, once weekly risedronate164 and once monthly ibandronate178
have been shown to increase BMD in the lumbar spine and femoral neck in men with
osteoporosis (T-score -2.0). Alendronate treatment was shown to reduce radiographic
vertebral fracture over 2 years.160,165 Similarly, risedronate treatment resulted in a decrease
of new vertebral fracture over 2 years.166 A once yearly infusion of IV zoledronate has been
shown to improve BMD similar to once weekly alendronate over 2 years.167
Teriparatide (rPTH)168 has been shown to be effective in the treatment of osteoporosis
in men. No fracture data is available in the teriparatide study.169
(Grade A, Level Ib)
Denosumab treatment for 1 year has been shown to increase BMD at the lumbar spine,
femoral neck, trochanter and distal one third radius in men with low bone mass.184
(Grade A, Level Ib)
Strontium ranelate treatment for 2 years has been shown to increase BMD at the lumbar
spine, femoral neck and total hip in men with osteoporosis.185
(Grade A, Level Ib)
The suggested pathway for the assessment and treatment of men with osteoporosis is
shown in Figure 2.
Recommendation
Men with osteoporosis should be investigated for secondary causes.
Bisphosphonates, and PTH, denosumab and strontium have been shown to
be effective, and androgen is useful in hypogonadal men.
(Grade A, Level Ib)
48
10. Implementing The Guidance
Although there is no health economic data with regards to the benefits of treating
osteoporosis from Malaysia, studies from the United States (US) and Europe have shown
that there is a personal and societal benefit to treating patients with osteoporosis. In Europe,
osteoporotic fractures are associated with more disability compared to rheumatoid arthritis,
hypertensive heart disease and breast cancer.174 Furthermore, the rate of osteoporotic hip
fractures has been shown to be increasing in Asia175 with associated increased costs.
In addition, the societal cost of osteoporosis has been increasing. In 1995, the cost of
osteoporotic fracture care in the US was US$13.8 billion and the proportion spent on
hospital, long term and outpatient care was similar.176 By 2005, the total annual cost of
osteoporosis fractures in the US is estimated to be US$16.9 billion of which 57% was spent
on hospital in-patient care, 30% on long term institution care and 13% on outpatient care.177
Existing facilitators for application of the recommendations in the Clinical Guidance include:
b) The availability of bone density measurement with DXA in the majority of General
Hospitals in Malaysia (public sector)
c) The availability of the Clinical Guidance in both hard copy for medical and
paramedical personnel [available from Malaysian Osteoporosis Society (MOS)
and via Continuing Medical Education programmes on the Guidance run by MOS]
and soft copy [on the websites of Ministry of Health, Academy of Medicine, MOS
and Malaysian Society of Rheumatology]
b) Apart from the Klang Valley area, there is limited availability of DXA outside the
capital towns in each state
c) The lack of availability of the full range of medications stated in the Clinical
Guidance in the public hospitals
To ensure that the Clinical Guidance is used, the following factors should be in place,
which have resource implications:
b) Provide training to all doctors (both at primary and secondary care levels) to
recognise and treat osteoporosis following an osteoporotic fracture (secondary
prevention)
49
c) Ensure that the screening tools e.g. OSTA are readily available in Health Clinics and
primary care clinics at major population centres
d) Ensure that there is easy availability of DXA machines, especially outside the Klang
Valley. This would require both investment in purchasing the machine as well as
training of the DXA technicians performing the scans. These DXA technicians will
continue to require regular continuing professional education to keep updated
f) Ensure availability of the drugs mentioned in the Clinical Guidance in the public as
well as private hospitals
To determine the number of low trauma/osteoporotic hip fractures that occur in the
major public and private hospitals in Malaysia prospectively and, of that baseline
number, to determine the number of patients put on osteoporosis treatment following
their hip arthroplasty to prevent future fractures.
12. Acknowledgements
The Working Group for this guidance would like to express their gratitude and
appreciation to the following for their contribution:
a) The panel of external reviewers who reviewed the draft
b) Dr Mohd Aminuddin bin Mohd Yusof, Senior Principal Assistant Director,
Medical Development Division, Health Technology Assessment Section,
Ministry Of Health, Malaysia
c) The Technical Advisory Committee for Clinical Practice Guidelines for their
valuable input and feedback
13. Disclosures
The authors of this guidance have no competing or conflicts of interest in this subject.
The development of this guidance has been totally funded by the Malaysian
Osteoporosis Society.
50
14. Appendix 1
Osteoporosis Self-Assessment Tool for Asians (OSTA)
Weight (kg)
Age 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90-94
40-44
45-49
50-54
65-69
70-74
Medium Risk
75-79
80-84
85-89
High Risk
90-94
95-99
Measure BMD#, if possible Measure BMD#, and consider BMD, measurement is proloably
Consider pharmacologic pharmacologic treatment not necessary unless other risk
treatment even if BMD is not availble170 if BMD is low170 factors are present* 170
If your patient is in the yellow or red region of the chart above, her risk of osteoporosis is
increased.
Note: Patients who have already had a non-traumatic fracture after menopause,
have approximately twice the risk of future fractures regardless of their age,
weight, or BMD, and should be considered for treatment.165 The risk of future
fractures is further increased if the patient also has low BMD.165
Other factors may increase risk regardless of her current age and weight
51
Appendix 2
Calcium Content of Some Common Foods34
52
Appendix 3
Evidence for the prevention of falls in older people
Adapted from Cryer C et al. London: Alliance for Better Bone Health, 2001172
Evidence grading:
1 Consistent findings in multiple randomized controlled trials (RCTs) or meta-analysis
2 Single RCT or weak inconsistent findings in multiple RCTs
3 Limited scientific evidence, cohort studies, flawed RCTs, panel consensus
Appendix 4
Chronic kidney disease Stages
53
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