Osteoporosis an update-Dr Selim

OSTEOPROSIS:
An Update
Dr Shahjada Selim
Associate Professor, Department of Endocrinology, BSMMU
Website: http://shahjadaselim.com

Osteoporosis and it’s impact
How osteoporosis is
diagnosed
Medications and update
1
2
3
5
Today’s Talk
Monitoring and follow up
Osteoporosis Update by Dr Selim

Bone & Bone Remodeling

Bone Homeostasis -
• the situation when the body requires and achieves an
equal amount of bone resorption and bone formation
 Up to 20 years-Formation>Resorption
 20-40 years -Formation=Resorption
 >4o years -Formation<Resorption
Bone Homeostasis

Continuous process –take place throughout the life.
This combined processes of breaking down bone and
building new bone are called Bone Remodeling. It is the
body’s way of maintaining bone homeostasis.
Bone Remodeling

Key functions/Purpose
1). to keep bone healthy by repairing damage caused by
normal wear and tear
2). transferring calcium and other ions into and out of the
skeleton and blood
Bone Remodeling

Bone Remodeling
During Infancy & Childhood
Bone formation exceeds resorption –
Increase in Bone Mass
During Puberty & early adulthood
Due to sex hormones – peak bone mass
achieved
During Age 25 – 35 Y
Resorbed bone replaced by an equal
amount of new Bone – Bone mass remains
constant
Between Age 35-50 Y
Resorption Bone exceeds formation – Bone
mass declines
As the person is older – Bone loss
accelerates due to declining estrogen level
in women

Osteoporosis & related issues

Definition:
A progressive systemic skeletal disorder characterized by
low bone mass and microarchitectural deterioration of
bone tissue with a consequent increase in bone fragility
and susceptibility to fracture.
Most commonly termed as “Porous Bone”
Osteoporosis
Occurs when the rate of bone resorption exceeds the rate of
bone formation – resulting a net loss of bone mass

Normal bone vs. Osteoporotic bone
• The normal bone shows a pattern
of strong interconnected plates
of bone.
• Much of this bone is lost in
Osteoporosis and the remaining
bone has a weaker rod-like
structure & some of the rods are
completely disconnected.
• These bits of disconnected bone
may be measured as bone mass
but contribute nothing to bone
strength.

Osteoporotic
Fracture
Burden

• Worldwide, osteoporosis-related fractures affect:
• Women: 1 in 3 aged 50+
• Men: 1 in 5 aged 50+
• Hip, spine and wrist fractures are the most common
• Women are at higher risk due to accelerated period of bone loss
following menopause
Burden
Cooper C et al. Healthy nutrition, healthy bones: How nutritional factors affect musculoskeletal health throughout life
• Fortunately, the right lifestyle and medical treatment makes a huge difference

ECONOMIC BURDEN
In USA:
• Health care costs continue to rise related to osteoporosis. Total
aggregate direct costs (ambulatory care, inpatient, prescription, other
health care costs) for all persons were $73.6 billion from 2012 to
2014, a rise of 118% from the $28.1 billion in 1998 to 2000, in 2014
dollars.
• The greatest change in average per-person cost was for
prescriptions, rising from $1771 in 1998 to 2000 to $3,494, in 2014
dollars, an increase of 97%.
3. Looker AC, Sarafrazi Isfajani N, Fan B, et al. Trends in osteoporosis and low bone mass in older US adults, 2005-2006 through 2013-2014. Osteoporos Int 2017;28(6):1979–88.
8. United States Bone and Joint Initiative: the burden of musculoskeletal diseases in the United States (BMUS). 4th edition. Rosemont (IL): 2019. Available at: http:// www.boneandjointburden.org. Accessed May 24, 2019.
9. Agency for Healthcare Research and Quality.Medical Expenditures Panel Survey (MEPS). U.S. Departmentof Health and Human Services, 1998-2014. Available at: http://meps.ahrq.gov/mespweb/.Accessed May 24, 2019.

Classification
1. Primary Osteoporosis –
more common, largely dependent on age & sex
a) Post-menopausal Osteoporosis
b) Senile Osteoporosis
2. Secondary Osteoporosis

Post-menopausal Senile
Type Type A Type B
Sex(es) affected Female Female & Male
Predisposing Factor Menopause Old Age
Age at onset
Up to 10 years after
menopause
Over age 65
Major Characteristic Estrogen defiency
Age-related bone
loss
Involved Bones
Often Trabecular (eg
spine)
Often Cortical (eg
hip)
Remodelling Abnormalities
Accelerated osteoclast
activity
Normal osteoclast
activity; Reduced
osteoblast activity
Primary Osteoporosis

– As a consequence of either an endocrine disease or a drug,
occuring in both sexes, children, adults
– Endocrine disorders, include excess production of
glucocorticoid & thyroid hormone, hypogonadism, and
diabetes
– Drugs include heparin, corticosteroids, thyroid hormone,
some diuretics, antacids, tetracyclines, and anticonvulsant
Secondary Osteoporosis

 Post-menopausal osteoporosis– Most common
 Osteoporosis may lead to fracture, which hampers the
QoL
 Wrists, spine & hip are the more susceptible areas to
fracture
 Fractures are the leading cause of death of
Osteoporotic patients
Points to remember►

Diagnosis

Investigations

Two major tools
• BMD [DEXA]:
–Diagnosis/ Status
–Treatment decision
• FRAX Tool (WHO)
–Risk assessment
–Treatment decision
Dennis M, NEJM 2016.

WHO Criteria
Kanis et al. J Bone Miner Res 1994; 9:1137-41
T-score
Normal - 1.0 and above
Osteopenia - 1.0 to - 2.5
Osteoporosis - 2.5 and below
Severe
(established)
osteoporosis
- 2.5 and below
plus one or more
osteoporotic fracture(s)

• Developed by the WHO
• Designed for primary care use
–in postmenopausal women and
–men older than 50 years
–(but validated for men and women aged 40–
90 years)

• Risk factors are combined with femoral
neck BMD to calculate 10 y probability of
fracture
–major osteoporotic
–hip fracture risk
NOF 2010 Osteoporosis Update by Dr Selim

• FDA–approves: therapy can be initiated
for patients with 10-year risk of
• hip fracture of at >3% or
• a risk of a major osteoporotic fracture
20% or higher.
FDA, NOF 2010 Osteoporosis Update by Dr Selim

Measures of Bone Mass (BMD)
• Others
– SXA (single x-ray absorptiometry) for forearm
– Quantitative computed tomography (QCT)
[measuring cortical and trabecular bone separately in
the lumbar spine and forearm]
– Broadband ultrasound attenuation (BUA), used to
make measurements in the calcaneum.
– Peripheral densitometry: By DEXA or QCT done in
obese patient at 1/3 (33%) radius site, fingers,
heel/calcaneus.
WHO, NOF, USPSTF Osteoporosis Update by Dr Selim
Axial DEXA is the most widely used method in clinical practice.

Biochemical Markers
• Bone-specific alkaline phosphatase
• Osteocalcin
• Urinary hydroxyproline
• Collagen crosslinks such as C-terminal-
telopeptide and N-terminal telopeptide
• Useful for aiding in osteoporosis diagnosis and
monitoring treatment response
Kasper et al. 2005, Kling et al 2014

Most useful Others
CBC, ESR Oestradiol, FSH
LFT Serum & Urine electrophoresis (BJP),
Punch out lesion X rays
RFT Endomysial ab, TTG ab, biopsy
Calcium, P, albumin, alk Phos, 24 h
U ca, PTH
U free cortisol, Overnight DST
Vitamin D Isotope bone scan
Thyroid function tests Albumin, cholesterol, Vit B12, folate, iron
profile
Testosterone, LH, SHBG
X-rays for evidence of previous
fractures/ fragility fracture
As appropriate for secondary causes
Kasper et al. 2005, Kling et al 2014
Others tests

• At appropriate age for sex.
• Having other risk of Primary
osteoporosis.
• At risk of developing secondary
osteoporosis.
• Having fragility fractures
Whom to Evaluate

Indication of BMD testing (AACE 2016)
• Other perimenopausal or
postmenopausal women with risk factors
for osteoporosis if willing to consider
pharmacologic interventions
– Low body weight (<57.6 kg or BMI <20
kg/m2)
– Ever use of long-term systemic
glucocorticoid therapy (≥3 mo)
– Family history of osteoporotic fracture
– Early menopause (< 40 yrs)
– Current smoking
– Excessive consumption of alcohol
• Secondary osteoporosis
• All women ≥65 years old
• All postmenopausal
women
– With H/O fracture(s)
without major trauma
– With osteopenia
identified
radiographically
– Starting or taking long-
term systemic
glucocorticoid therapy
(≥3 mo)

Indication of BMD testing (NOF 2019)
• Women age ≥65 y and men age ≥70 y, regardless of clinical risk
factors
• Younger postmenopausal women (<40 y), women in the
menopausal transition and men age 50-69 y with clinical risk
factors for fracture
• Adults who have a fracture after age 50 y
• Adults with a condition (e.g. RA) or taking a medication (e.g. ≥ 5
mg prednisone or equivalent/day for ≥ 3 mo) associated with
low bone mass or bone loss

DEXA scoring
 T score : How many standard deviation of patient’s BMD value
differ from that of young healthy adult of same sex.
 Z score : How many standard deviation of patient’s BMD value
differ from that of individual of same age and sex. Low Z score
suggest secondary cause of osteoporosis but normal Z score do
not rule out the possibility of underlying disorder.

Limitations of DEXA
• PA measurement at lumbar spine in older patient are subject to
error due to -
– Osteoarthritic change
– Aortic calcification
– Previous fracture
– Radiodense material e.g. surgical implant
– Severe scoliosis
– Extreme obesity
• Overcome by performing lateral densiometry of lumbar spine but
this measurement is less precise.
• Due to sources of error present in measurement of lumbar spine,
↑reliance is placed on measurement derived from hip.

WHO criteria for postmenopausal women
T score Category
At or above -1 SD Normal
Between -1 and -2.5 SD Osteopenia
At or below -2.5 SD Osteoporosis
At or below -2.5 SD with H/O
fragility fracture.
Severe
osteoporosis

Medications and updates

Non pharmacological treatment of osteoporosis
• Adequate intake of dietary calcium (1200 mg/day) and Vitamin D
(800-1000 IU/day).
• Serum 25 (OH) D should be ≥30 ng/ml/ ≥75 nmol/L.
• Calcium rich food : Milk and milk products, liver, egg yolk, fish oil.
• Regular exercise. Both lack of exercise and excessive exercise
cause osteoporosis.
• Avoid smoking and alcohol.
• Review of medication : Corticosteroid is truely needed or not,
keep dosage and duration to the minimum. if patient on
thyroxine. FT4, TSH measured to avoid over dose.

Age Sex Recommended
dietary allowance (mg/d)
0-6 mo M + F 200
6-12 mo M + F 260
1-3 y M + F 700
4-8 y M + F 1000
9-18 y M + F 1300
19-50 y M + F 1000
51-70 y M 1000
51-70 y F 1200
71+ y M + F 1200
Recommended dietary allowance for Calcium

Fall prevention
• Balance and exercise training.
• Rationalisation of medication: Avoidance of unnecessary
sedative, drugs causing postural hypotension, polypharmacy.
• Home environment hazard correction :
– Grab bars in bath rooms
– Hand rails on stair
– Non slippery tiles
– Indoor and outdoor carpeting.
– ↑ ligh ng in high risk areas - bathrooms, stair
– Walking aid
– Correction of visual impairment, neurological problem.

Indication of pharmacological treatment (NOF)
Post menopausal women and men age 50 years or
older presenting with –
• Hip or spine fracture (Either clinical or radiological)
• T score -2.5 or below at spine or femoral neck.
• T score between -1 and -2.5 at spine or femoral neck and 10
year probability of hip fracture ≥3% or major osteoporosis
related fracture ≥20% (Humerus, forearm, hip, vertebral) based
on FRAX tool

US FDA Approved drugs for osteoporosis
• Bisphosphonates : Alendronate, Risedronate,
Ibandronate, , Zolendronic acid
• Calcitonin
• Estrogen/HRT
• Selective estrogen receptor modulator (Raloxifene)
• RANKL inhibitor (Denosumab)
• Teriparatide/recombinant human PTH (1-34)

Drugs Postmenopausal osteoporosis
Prevention Treatment
Alendronate (Ostel D 70/2800) 5 mg PO daily
35 mg PO weekly
10 mg PO daily
70 mg PO weekly
Risedronate (Salost 5, 35, 150 mg) 5 mg PO daily
35 mg PO weekly
5 mg PO daily
35 mg PO weekly
Ibandronate (Bondrova) 150 mg PO monthly 150 mg PO monthly
Zolendronic acid (Aclasta, Bonizol) 5 mg IV every
2nd year
5 mg IV yearly
Calcitonin (Salmon Calcitonin)
Miacalcic nasal spray
- 200 IU/spray on alternate
nostril once daily
Estrogen Multiple formulations
Raloxifene (Ralox 60 mg) 60 mg PO daily 60 mg PO daily
Denosumab (Denosis) - 60 mg s.c. every 6 month
Teriparatide (Forteo) - 20 µg s.c. daily
Drugs and Dosages

Drugs Fracture risk reduction
Vertebral Non vertebral Hip
Alendronate Yes Yes Yes
Risedronate Yes Yes Yes
Ibandronate Yes No effect demonstrated
Zolendronic acid Yes Yes Yes
Calcitonin (Salmon
Calcitonin)
Yes No effect demonstrated
Estrogen Yes Yes Yes
Raloxifene Yes No effect demonstrated
Denosumab Yes Yes Yes
Teriparatide Yes Yes No
Drug Selecting for Osteoporosis

Swallowing of bisphosphonate
• On empty stomach at morning with a full glass of plain
water (at least 8 Oz of water).
• Patient should remain upright (sitting or standing) for at
least 30 minutes after talking tablet.
• Nothing other than plain water should be taken for 30
minutes (for Alendronate and Risedronate) or 60 minutes
(for Ibandronate).
• The absorption of orally administered bisphosphonates is
<1%. Taking with food substantially reduce the absorption
of the drug.

Adverse effect of bisphosphonates
• Esophageal irritation: Esophagitis, esophageal erosion, ulcer,
bleeding, perforation and ? association with esophageal cancer.
• IV bisphosphonate : Acute phase reactions in 30-40% of patient at
first dose, <2% in subsequent doses or patient who received
previously oral bisphosphonate. Fever, myalgia, headache,
arthralgia lasting several days.
• Osteonecrosis of jaw
• Atypical femur fracture
• Uveitis
• Atrial fibrillation (Zolendronic acid)

Osteonecrosis of jaw
• In patient receiving IV or oral bisphosphonate and Denosumab, common in
patient receiving higher dose (10 times of osteoporosis dose) for malignancy.
• For osteoporosis dose, incidence 1/10000 to 1/1 lac patients/year.
• Presence of necrotic bone in mandible or maxilla typically occurring after
tooth extraction when the socket fails to heal within 8 weeks.
• Risk factors include poor dental hygiene, dental pathologic conditions,
invasive dental procedure, infections, diabetes.
• Risk can be reduced by - good oral hygiene, avoid invasive dental procedure.
It is better to do a comprehensive dental check up before therapy.

Osteonecrosis of jaw

Atypical subtrochanteric femur fracture/Chalk stick fracture
• In patients on long-term bisphosphonate
therapy (>5 years).
• located along femoral diaphysis from just distal
to the lesser trochanter to just proximal to the
supracondylar flare
• occur after little or no trauma
• Imaging study should be done if persistent
thigh or groin pain in patient with H/O
Bisphosphonate therapy.
• Substantially transverse in its orientation
• Often bilateral (28%)

Contraindications of bisphosphonate
• Anatomic or functional esophageal
abnormalities eg. Achalasia, stricture.
• Renal impairment (GFR <35 ml/min)
• Hypocalcaemia
• Pregnancy and breast feeding
• Hypersensitivity to bisphosphonate

Precaution for Zolendronic acid
• Renal function (creatinine, CCR) and cardiac status
(ECG) should be assessed before administering
zolendronic acid.
• Pre existing hypocalcemia should be corrected.
• Appropriately hydrated prior to and following
administration of zolendronic acid.
• Serum calcium and creatinine should be monitored.

Calcitonin
• Injectable and nasal spray of recombinant
salmon calcitonin .
• Inhibitor of osteoclastic bone resorption,
also provide some analgesic effect.
• Adverse effects of nasal spray is rhinitis,
epistaxis.

Estrogen/HRT
• HRT may still be appropriate for treatment of
menopausal symptoms.
• Prevention of osteoporosis no longer considered as
primary indication.
• Used only when non-estrogen medication is not
considered to be appropriate.
• When estrogen is prescribed for a patient who still has
uterus, a progesterone also should be used to protect
against endometrial proliferation.

Selective estrogen receptor modulator
(SERM) Raloxifene
• Act as estrogen against on some tissues but
antagonist on others.
• Raloxifene reduces the risk of breast cancer,
so good choice for patients who are at high
risk of breast cancer.
• Adverse effects is venous thromboembolic
disease.

Denosumab
• Human monoclonal antibody to RANK-L (receptor
activator of nuclear factor kappa-B ligand).
• Prevents RANKL from binding to its receptor, RANK and
reduce differentiation of precursor cells into mature
osteoclasts and decreasing function and survival of
activated osteoclasts.
• Hypocalcemia must be corrected before starting
denosumab.
• Adverse effects is serious infections including skin
infection.

Emerging therapy

Recombinant Human PTH ( 1-34 )
Teriparatide
• Persistent elevation of PTH cause osteoporosis
as in primary hyperparathyroidism but
intermittent elevation of PTH causes net bone
gain.
• Anabolic agent, by contrast, the medications
discussed previously appear to work by
reducing bone resorption (Antiresorptive)
• 20 µg s.c. daily.

• Measure serum Calcium, PTH, 25(OH) D before
treatment with teriparatide.
• Adverse effects : Mild hypercalcemia (monitor Calcium),
osteosarcoma.
• Contraindications : Pa ent with ↑ed risk of
osteosarcoma -
Paget disease of bone
Unexplained elevation of ALP
Teriparatide

Monitoring and follow up

• Biochemical markers of bone turnover change 3-
6 months after therapy.
• Significant reductions in BTMs are seen with
anti-resorptive therapy and have been
associated with fracture reduction and
significant increases indicate good response to
anabolic therapy.
• DEXA of PA spine and hip (Total hip or femoral
neck ) is gold standard.

• Repeat DEXA every 1-2 years until findings are stable.
Continue with follow-up DEXA every 1-2 years or at a
less-frequent interval depending on clinical
circumstances.
• As rich in trabecular bone, PA spine is more metabolically
active and respond early to therapy and best site for
monitoring than hip.
• Monitoring should be done at same facility with use of
same machine preferably by same technician and should
involve the same region of interest.

• ↓ BMD or new fragility fracture : Non compliance,
secondary cause of bone loss, new medication that may
cause bone loss.
• Fracture during drug therapy does not indicate treatment
failure as most effective treatment only reduce fracture
risk by 25-50%.
• Accurate yearly height measurement is needed. Patients
who lose 2 cm or more in height either acutely or
cumulatively should have a repeat vertebral imaging.

How Long Should Patients Be Treated?
• For oral bisphosphonates, consider a “bisphosphonate
holiday” after 5 years of stability in moderate-risk
patients or 6-10 years of stability in higher-risk patients.
• For Zoledronic acid, consider a drug holiday after 3
annual doses in moderate-risk patients and after 6
annual doses in higher-risk patients.
• Treatment with teriparatide should be limited to 2 years.

• Teriparatide or Raloxifene may be used during
“bisphosphonate holiday” period for higher-risk patients.
• A drug “holiday” is not recommended with denosumab.
• The ending of the “holiday” for bisphosphonate treatment
should be based on individual patient circumstances
(fracture risk or change in BMD or BTMs).
• Other therapeutic agents should be continued for as long as
clinically appropriate.

Is combination therapy better?
• AACE does not recommend concomitant use of drugs for
prevention or treatment of postmenopausal osteoporosis.
• If Estrogen is being given for treatment of menopausal symptoms
or Raloxifene is administered to reduce the risk of breast cancer
an additional agent such as a Bisphosphonate, Denosumab or
Teriparatide may be considered in higher-risk patients.
• Combined Denosumab and Teriparatide achieves a better BMD
response versus either agent alone but no fracture data are
available.

Sequential use of therapeutic agents?
• Treatment with teriparatide should always be
followed by antiresorptive agents to prevent
bone density decline and loss of fracture
efficacy.

Vertebral augmentation for Compression fractures?
• Vertebroplasty and kyphoplasty are not
recommended as first-line treatment of vertebral
fractures given the unclear benefit on overall pain
and increased risk of vertebral fractures in adjacent
vertebrae.

Osteoporosis management in CKD
• Highly controversial.
• Target is mainly focused to keep serum Calcium, phosphate,
Vitamin D and serum PTH within target.
• Bisphosphonates : Efficacy unknown, especially long-term use,
safety data lacking, theoretically dangerous in adynamic bone
disease and should have a bone biopsy.
• Estrogen, Selective estrogen receptor modulators (SERMs) :
Efficacy unknown, safety data lacking
• Calcitonin : Probably safe but this therapy has to be considered in
light of uncertain efficacy.

Prevention of Osteoporosis

Calcium and Vitamin D Intake
Recommendations
Life Stage Group
Recommended
Dietary Allowance of
vitamin D (IU/day)
Recommended
Dietary Allowance
Calcium (mg/day)
19–50 years old 600 1,000
31–50 years old 600 1,000
51–70-year-old male 600 1,000
51–70-year-old female 600 1,200
>70 years old 700 1,200
Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D: Report Brief. Washington, DC: IOM; 2010. Available at:
http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx. Accessed September 13, 2013.

The good news: Osteoporosis is preventable for
most people!
• Healthy diet and
lifestyle are important
for BOTH men and
women.
• Osteoporosis is
detectable and
treatable

Thanks for your patience
THANKS

Osteoporosis an update-Dr Selim

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