Final Project PDF

Chapter-One
Introduction
Page | 1
Literature Review on Drug Induced Osteoporosis
1.1. Definition
The word "osteoporosis" is from the Greek terms for "porous bones". Osteoporosis is
a disease in which bone weakening increases the risk of a broken bone. It is the most common
reason for a broken bone among the elderly. Bones that commonly break include the vertebrae in
the spine, the bones of the forearm, and the hip. Until a broken bone occurs there are typically no
symptoms. Bones may weaken to such a degree that a break may occur with minor stress or
spontaneously. Chronic pain and a decreased ability to carry out normal activities may occur
following a broken bone.
Osteoporosis may be due to lower-than-normal maximum bone mass and greater-than-normal

bone loss. Bone loss increases after menopause due to lower levels of estrogen. Osteoporosis
may also occur due to a number of diseases or treatments, including alcoholism, anorexia,
hyperthyroidism, kidney disease, and surgical removal of the ovaries. Certain medications
increase the rate of bone loss, including some antiseizure medications, chemotherapy, proton
pump inhibitors, selective serotonin reuptake inhibitors, and glucocorticosteroids. Smoking and
too little exercise are also risk factors. Osteoporosis is defined as a bone density of 2.5 standard
deviations below that of a young adult. This is typically measured by dual-energy X-ray
absorptiometry.
Prevention of osteoporosis includes a proper diet during childhood and efforts to avoid
medications that increase the rate of bone loss. Efforts to prevent broken bones in those with
osteoporosis include a good diet, exercise, and fall prevention. Lifestyle changes such as
stopping smoking and not drinking alcohol may help. Biphosphonate medications are useful in
those with previous broken bones due to osteoporosis. In those with osteoporosis but no previous
broken bones, they are less effective. A number of other medications may also be useful.
Osteoporosis becomes more common with age. About 15% of Caucasians in their 50s and 70%
of those over 80 are affected. It is more common in women than men. In the developed world,
depending on the method of diagnosis, 2% to 8% of males and 9% to 38% of females are
affected. Rates of disease in the developing world are unclear. About 22 million women and 5.5
million men in the European Union had osteoporosis in 2010. In the United States in 2010, about
eight million women and one to two million men had osteoporosis. White and Asian people are
at greater risk.
Page | 2
1.2. Causes of Osteoporosis
Osteoporosis occurs when there is an imbalance between new bone formation and old bone
resorption. The body may fail to form enough new bone, or too much old bone may be
reabsorbed, or both. Two essential minerals for normal bone formation are calcium and
phosphate. Throughout youth, the body uses these minerals to produce bones. Calcium is
essential for proper functioning of the heart, brain, and other organs. To keep those critical
organs functioning, the body reabsorbs calcium that is stored in the bones to maintain blood
calcium levels. If calcium intake is not sufficient or if the body does not absorb enough calcium
from the diet, bone production and bone tissue may suffer. Thus, the bones may become weaker,
resulting in fragile and brittle bones that can break easily.
Usually, the loss of bone occurs over an extended period of years. Often, a person will sustain a
fracture before becoming aware that the disease is present. By then, the disease may be in its
advanced stages and damage may be serious.
The leading cause of osteoporosis is a lack of certain hormones, particularly estrogen in women
and androgen in men. Women, especially those older than 60 years of age, are frequently
diagnosed with the disease. Menopause is accompanied by lower estrogen levels and increases a
woman's risk for osteoporosis. Other factors that may contribute to bone loss in this age group
include inadequate intake of calcium and vitamin D, lack of weight-bearing exercise, and other
age-related changes in endocrine functions (in addition to lack of estrogen).
Other conditions that may lead to osteoporosis include overuse of corticosteroids (Cushing
syndrome), thyroid problems, lack of muscle use, bone cancer, certain genetic disorders, use of
certain medications, and problems such as low calcium in the diet.
Page | 3
Figure No : 01. Graph bone mass in men & women
1.3. Signs & Symptoms of Osteoporosis
Osteoporosis itself has no symptoms; its main consequence is the increased risk of bone
fractures. Osteoporotic fractures occur in situations where healthy people would not normally
break a bone; they are therefore regarded as fragility fractures. Typical fragility fractures occur
in the vertebral column, rib, hip and wrist.
Figure No : 02. Human skeleton
Page | 4
1.3.1. Fractures
Fractures are a common symptom of osteoporosis and can result in disability. Acute and chronic
pain in the elderly is often attributed to fractures from osteoporosis and can lead to further
disability and early mortality. These fractures may also be asymptomatic. The most common
osteoporotic fractures are of the wrist, spine, shoulder and hip. The symptoms of a vertebral
collapse ("compression fracture") are sudden back pain, often with radicular pain (shooting pain
due to nerve root compression) and rarely with spinal cord compression or cauda equina
syndrome. Multiple vertebral fractures lead to a stooped posture, loss of height, and chronic pain
with resultant reduction in mobility.
Fractures of the long bones acutely impair mobility and may require surgery. Hip fracture, in
particular, usually requires prompt surgery, as serious risks are associated with it, such as deep
vein thrombosis and pulmonary embolism, and increased mortality.
Fracture risk calculators assess the risk of fracture based upon several criteria, including bone
mineral density, age, smoking, alcohol usage, weight, and gender. Recognized calculators
include FRAX and Dubbo.
The term "established osteoporosis" is used when a broken bone due to osteoporosis has
occurred. Osteoporosis is a part of frailty syndrome.
Figure No : 03. Fractures of bone

Page | 5
1.3.2. Fractures of the Spine
Vertebral (spinal) compression fractures are broken bones in the back that are due to weak bones
caused by osteoporosis. The vertebrae (spinal bone) collapses as a result of even minor injuries
related to falling, bending, twisting, or sneezing. As the bones of the spine lose their
mineralization and strength, they can collapse, causing a hunched-over appearance, often
referred to as a "dowager hump."
Figure No : 04. Fractures of spine

Page | 6
1.3.3. Stress Fracture
Stress fractures occur in bones due to repetitive injuries, usually with minimal trauma. Patients
with osteoporosis are more prone to stress fractures because of the weakness of their bones.
Figure No : 05. Stress fracture
1.3.4. Hip Fracture
Patients with osteoporosis are at greater risk for hip fractures. Even a simple fall can cause a hip
fracture in a person with osteoporosis. Due to the weakness in the bones these injuries may take a
long time or be difficult to fully heal.
Figure No : 06. Hip fracture

Page | 7
1.4. Factors Determine Bone Strength
Bone strength is related to bone mass (density), which refers to the amount of mineralization
remaining in bones as people age. The denser the bones, the stronger they are.
Figure No : 07. Bone density deterioration
Factors that determine bone strength include:
 Genetics
 Environment
 Medications
 Ethnicity (African-Americans have higher bone density than Caucasians or Asians)
 Gender (men have higher bone density than women)
 Aging (bone density reaches its peak around age 25, and decreases after age 35)
1.5. Risk Factors of Osteoporosis
Risk factors for osteoporotic fracture can be split between nonmodifiable and (potentially)
modifiable. In addition, osteoporosis is a recognized complication of specific diseases and
disorders. Medication use is theoretically modifiable, although in many cases, the use of
medication that increases osteoporosis risk may be unavoidable. Caffeine is not a risk factor for
osteoporosis. It is more common in females than males.
Page | 8
1.5.1. Nonmodifiable
The most important risk factors for osteoporosis are advanced age (in both men and women)
and female sex; estrogen deficiency following menopause or surgical removal of the ovaries is
correlated with a rapid reduction in bone mineral density, while in men, a decrease in
testosterone levels has a comparable (but less pronounced) effect.
 Ethnicity: While osteoporosis occurs in people from all ethnic groups, European or
Asian ancestry predisposes for osteoporosis.
 Heredity: Those with a family history of fracture or osteoporosis are at an increased risk;
the heritability of the fracture, as well as low bone mineral density, is relatively high,
ranging from 25 to 80%. At least 30 genes are associated with the development of
osteoporosis. Those who have already had a fracture are at least twice as likely to have
another fracture compared to someone of the same age and sex.
 Build: A small stature is also a nonmodifiable risk factor associated with the
development of osteoporosis.
Figure No : 08. Bone density peaks (male & female)
Page | 9
1.5.2. Potentially modifiable
 Excessive alcohol: Although small amounts of alcohol are probably beneficial (bone
density increases with increasing alcohol intake), chronic heavy drinking (alcohol intake
greater than three units/day) probably increases fracture risk despite any beneficial effects
on bone density.
 Vitamin D deficiency: Low circulating Vitamin D is common among the elderly
worldwide. Mild vitamin D insufficiency is associated with increased parathyroid
hormone (PTH) production. PTH increases bone resorption, leading to bone loss. A
positive association exists between serum 1,25-dihydroxycholecalciferol levels and bone
mineral density, while PTH is negatively associated with bone mineral density.
 Tobacco smoking: Many studies have associated smoking with decreased bone health,
but the mechanisms are unclear. Tobacco smoking has been proposed to inhibit the
activity of osteoblasts, and is an independent risk factor for osteoporosis. Smoking also
results in increased breakdown of exogenous estrogen, lower body weight and earlier
menopause, all of which contribute to lower bone mineral density.
 Malnutrition: Nutrition has an important and complex role in maintenance of good
bone. Identified risk factors include low dietary calcium and/or phosphorus, magnesium,
zinc, boron, iron, fluoride, copper, vitamins A, K, E and C (and D where skin exposure to
sunlight provides an inadequate supply). Excess sodium is a risk factor. High blood
acidity may be diet-related, and is a known antagonist of bone. Some have identified low
protein intake as associated with lower peak bone mass during adolescence and lower
bone mineral density in elderly populations. Conversely, some have identified low
protein intake as a positive factor, protein is among the causes of dietary acidity.
Imbalance of omega-6 to omega-3 polyunsaturated fats is yet another identified risk
factor.
 High dietary protein from animal sources: Research has found an association between
diets high in animal protein and increased urinary calcium, and have been linked to an
increase in fractures. However, the relevance of this observation to bone density is
unclear, since higher protein diets tend to increase absorption of calcium from the diet
and are associated with higher bone density. Indeed, it has recently been argued that low
Page | 10
protein diets cause poor bone health. No interventional trials have been performed on
dietary protein in the prevention and treatment of osteoporosis.
 Underweight/inactive: Bone remodeling occurs in response to physical stress, so
physical inactivity can lead to significant bone loss. Weight bearing exercise can increase
peak bone mass achieved in adolescence, and a highly significant correlation between
bone strength and muscle strength has been determined. The incidence of osteoporosis is
lower in overweight people.
 Endurance training: In female endurance athletes, large volumes of training can lead to
decreased bone density and an increased risk of osteoporosis. This effect might be caused
by intense training suppressing menstruation, producing amenorrhea, and it is part of
the female athlete triad. However, for male athletes, the situation is less clear, and
although some studies have reported low bone density in elite male endurance
athletes, others have instead seen increased leg bone density.
 Heavy metals: A strong association between cadmium and lead with bone disease has
been established. Low-level exposure to cadmium is associated with an increased loss of
bone mineral density readily in both genders, leading to pain and increased risk of
fractures, especially in the elderly and in females. Higher cadmium exposure results
in osteomalacia (softening of the bone).
 Soft drinks: Some studies indicate soft drinks (many of which contain phosphoric acid)
may increase risk of osteoporosis, at least in women. Others suggest soft drinks may
displace calcium-containing drinks from the diet rather than directly causing
osteoporosis.
 Proton pump inhibitors (such as lansoprazole, esomeprazole, or omeprazole) that
decrease stomach acid, are a risk for bone fractures if taken for two or more years, due to
decreased absorption of calcium in the stomach.
1.5.3. Medical disorders
Many diseases and disorders have been associated with osteoporosis. For some, the underlying
mechanism influencing the bone metabolism is straightforward, whereas for others the causes are
multiple or unknown.
Page | 11
In general, immobilization causes bone loss (following the 'use it or lose it' rule). For example,
localized osteoporosis can occur after prolonged immobilization of a fractured limb in a cast.
This is also more common in active people with a high bone turn-over (for example, athletes).
Other examples include bone loss during space flight or in people who are bedridden or use
wheelchairs for various reasons.
Hypogonadal states can cause secondary osteoporosis. These include Turner syndrome,
Klinefelter syndrome, Kallmann syndrome, anorexia nervosa, andropause, hypothalamic
amenorrhea or hyperprolactinemia. In females, the effect of hypogonadism is mediated by
estrogen deficiency. It can appear as early menopause (<45 years) or from prolonged
premenopausal amenorrhea (>1 year). Bilateral oophorectomy (surgical removal of the ovaries)
and premature ovarian failure cause deficient estrogen production. In males, testosterone
deficiency is the cause (for example, andropause or after surgical removal of the testes).
Endocrine disorders that can induce bone loss include Cushing's syndrome, hyperparathyroidism,
hyperthyroidism, hypothyroidism, diabetes mellitus type 1 and 2, acromegaly, and adrenal
insufficiency.
Malnutrition, parenteral nutrition and malabsorption can lead to osteoporosis. Nutritional and
gastrointestinal disorders that can predispose to osteoporosis include undiagnosed and
untreated coeliac disease (both symptomatic and asymptomatic people), Crohn's disease,
ulcerative colitis, cystic fibrosis, surgery (after gastrectomy, intestinal bypass surgery or bowel
resection) and severe liver disease (especially primary biliary cirrhosis). People with lactose
intolerance or milk allergy may develop osteoporosis due to restrictions of calcium-containing
foods. Individuals with bulimia can also develop osteoporosis. Those with an otherwise adequate
calcium intake can develop osteoporosis due to the inability to absorb calcium and/or vitamin D.
Other micronutrients such as vitamin K or vitamin B12 deficiency may also contribute.
People with rheumatologic disorders such as rheumatoid arthritis, ankylosing spondylitis,

systemic lupus erythematosus and polyarticular juvenile idiopathic arthritis are at increased risk
of osteoporosis, either as part of their disease or because of other risk factors (notably
corticosteroid therapy). Systemic diseases such as amyloidosis and sarcoidosis can also lead to
osteoporosis.
Page | 12
Chronic kidney disease can lead to renal osteodystrophy.
Hematologic disorders linked to osteoporosis are multiple myeloma and other monoclonal
gammopathies, lymphoma, leukemia, mastocytosis, hemophilia, sickle-cell disease and
thalassemia.
Several inherited disorders have been linked to osteoporosis. These include osteogenesis
imperfecta, Marfan syndrome, hemochromatosis, hypophosphatasia (for which it is often
misdiagnosed), glycogen storage diseases, homocystinuria, Ehlers–Danlos syndrome,
porphyria, Menkes' syndrome, epidermolysis bullosa and Gaucher's disease.
People with scoliosis of unknown cause also have a higher risk of osteoporosis. Bone loss can be
a feature of complex regional pain syndrome. It is also more frequent in people with Parkinson's
disease and chronic obstructive pulmonary disease.
People with Parkinson's disease have a higher risk of broken bones. This is related to poor
balance and poor bone density. In Parkinson’s disease there may be a link between the loss
of dopaminergic neurons and altered calcium metabolism (and iron metabolism) causing a
stiffening of the skeleton and kyphosis.
Figure No : 09. Calcium homeostasis

Page | 13
The body regulates calcium homeostasis with two pathways; one is signaled to turn on when
blood calcium levels drop below normal and one is the pathway that is signaled to turn on when
blood calcium levels are elevated.
1.5.4. Medication
Certain medications have been associated with an increase in osteoporosis risk; only
glucocorticosteroids and anticonvulsants are classically associated, but evidence is emerging
with regard to other drugs.
Steroid-induced osteoporosis (SIOP) arises due to use of glucocorticoids – analogous to

Cushing's syndrome and involving mainly the axial skeleton. The synthetic glucocorticoid
prescription drug prednisone is a main candidate after prolonged intake. Some professional
guidelines recommend prophylaxis in patients who take the equivalent of more than 30 mg
hydrocortisone (7.5 mg of prednisolone), especially when this is in excess of three months. It is
recommended to use calcium or Vitamin D as prevention. Alternate day use may not prevent this
complication.
Barbiturates, phenytoin and some other enzyme-inducing antiepileptics – these probably

accelerate the metabolism of vitamin D.
L-Thyroxine over-replacement may contribute to osteoporosis, in a similar fashion as

thyrotoxicosis does. This can be relevant in subclinical hypothyroidism.
Several drugs induce hypogonadism, for example aromatase inhibitors used in breast cancer,
methotrexate and other antimetabolite drugs, depot progesterone and gonadotropin-releasing
hormone agonists.
Anticoagulants- long-term use of heparin is associated with a decrease in bone density,

and warfarin (and related coumarins) have been linked with an increased risk in osteoporotic
fracture in long-term use.
Proton pump inhibitors- these drugs inhibit the production of stomach acid; this is thought to
interfere with calcium absorption. Chronic phosphate binding may also occur with aluminium-
containing antacids.
Page | 14
Thiazolidinediones (used for diabetes) – rosiglitazone and possibly pioglitazone, inhibitors
of PPAR, have been linked with an increased risk of osteoporosis and fracture.
Chronic lithium therapy has been associated with osteoporosis.
1.5.5. Evolutionary
Age-related bone loss is common among humans due to exhibiting less dense bones than other
primate species. Because of the more porous bones of humans, frequency of severe osteoporosis
and osteoporosis related fractures is higher. The human vulnerability to osteoporosis is an
obvious cost but it can be justified by the advantage of bipedalism inferring that this
vulnerability is the byproduct of such. It has been suggested that porous bones help to absorb the
increased stress that we have on two surfaces compared to our primate counterparts who have
four surfaces to disperse the force. In addition, the porosity allows for more flexibility and a
lighter skeleton that is easier to support. One other consideration may be that diets today have
much lower amounts of calcium than the diets of other primates or the tetrapedal ancestors to
humans which may lead to higher likelihood to show signs of osteoporosis.
1.6. Pathogenesis
The underlying mechanism in all cases of osteoporosis is an imbalance between bone

resorption and bone formation. In normal bone, matrix remodeling of bone is constant; up to
10% of all bone mass may be undergoing remodeling at any point in time. The process takes
place in bone multicellular units (BMUs) as first described by Frost & Thomas in 1963.
Osteoclasts are assisted by transcription factor PU.1 to degrade the bone matrix,
while osteoblasts rebuild the bone matrix. Low bone mass density can then occur when
osteoclasts are degrading the bone matrix faster than the osteoblasts are rebuilding the bone.
The three main mechanisms by which osteoporosis develops are an inadequate peak bone mass
(the skeleton develops insufficient mass and strength during growth), excessive bone resorption,
and inadequate formation of new bone during remodeling, likely due to MSC biasing away from
the osteoblast and toward the marrow adipocyte lineage. An interplay of these three mechanisms
underlies the development of fragile bone tissue. Hormonal factors strongly determine the rate of
bone resorption; lack of estrogen (e.g. as a result of menopause) increases bone resorption, as
Page | 15
well as decreasing the deposition of new bone that normally takes place in weight-bearing bones.
The amount of estrogen needed to suppress this process is lower than that normally needed to
stimulate the uterus and breast gland. The form of the estrogen receptor appears to be the most
important in regulating bone turnover. In addition to estrogen, calcium metabolism plays a
significant role in bone turnover, and deficiency of calcium and vitamin D leads to impaired
bone deposition; in addition, the parathyroid glands react to low calcium levels by secreting
parathyroid hormone (parathormone, PTH), which increases bone resorption to ensure sufficient
calcium in the blood. The role of calcitonin, a hormone generated by the thyroid that increases
bone deposition, is less clear and probably not as significant as that of PTH.
Figure No : 10. Pathogenesis of osteoporotic fractures
The activation of osteoclasts is regulated by various molecular signals, of

which RANKL (receptor activator of nuclear factor kappa-B ligand) is one of the best studied.
This molecule is produced by osteoblasts and other cells (e.g. lymphocytes), and
stimulates RANK (receptor activator of nuclear factor B). Osteoprotegerin (OPG) binds RANKL
before it has an opportunity to bind to RANK, and hence suppresses its ability to increase bone
Page | 16
resorption. RANKL, RANK and OPG are closely related to tumor necrosis factor and its
receptors. The role of the Wnt signaling pathway is recognized, but less well understood. Local
production of eicosanoids and interleukins is thought to participate in the regulation of bone
turnover, and excess or reduced production of these mediators may underlie the development of
osteoporosis.
Trabecular bone (or cancellous bone) is the sponge-like bone in the ends of long bones and
vertebrae. Cortical bone is the hard outer shell of bones and the middle of long bones. Because
osteoblasts and osteoclasts inhabit the surface of bones, trabecular bone is more active and is
more subject to bone turnover and remodeling. Not only is bone density decreased, but the
microarchitecture of bone is also disrupted. The weaker spicules of trabecular bone break
("microcracks"), and are replaced by weaker bone. Common osteoporotic fracture sites, the
wrist, the hip and the spine, have a relatively high trabecular bone to cortical bone ratio. These
areas rely on the trabecular bone for strength, so the intense remodeling causes these areas to
degenerate most when the remodeling is imbalanced. Around the ages of 30–35, cancellous or
trabecular bone loss begins. Women may lose as much as 50%, while men lose about 30%.
Figure No : 11. Osteoporosis locations
Page | 17
Light micrograph of an osteoclast displaying typical distinguishing characteristics: a large cell
with multiple nuclei and a "foamy" cytosol.
Figure No : 12. Osteoclast
Light micrograph of osteoblasts, several displaying a prominent Golgi apparatus, actively

synthesizing osteoid containing two osteocytes.
Figure No : 13. Osteoblast
Page | 18
1.7. Diagnosis of Osteoporosis
The diagnosis of osteoporosis can be made using conventional radiography and by measuring the
bone mineral density (BMD). The most popular method of measuring BMD is dual-energy X-ray
absorptiometry.
In addition to the detection of abnormal BMD, the diagnosis of osteoporosis requires

investigations into potentially modifiable underlying causes; this may be done with blood tests.
Depending on the likelihood of an underlying problem, investigations for cancer with metastasis
to the bone, multiple myeloma, Cushing's disease and other above-mentioned causes may be
performed.
1.7.1. Conventional radiography
Conventional radiography is useful, both by itself and in conjunction with CT or MRI, for
detecting complications of osteopenia (reduced bone mass; pre-osteoporosis), such as fractures;
for differential diagnosis of osteopenia; or for follow-up examinations in specific clinical
settings, such as soft tissue calcifications, secondary hyperparathyroidism, or osteomalacia in
renal osteodystrophy. However, radiography is relatively insensitive to detection of early disease
and requires a substantial amount of bone loss (about 30%) to be apparent on X-ray images.
The main radiographic features of generalized osteoporosis are cortical thinning and increased
radiolucency. Frequent complications of osteoporosis are vertebral fractures for which spinal
radiography can help considerably in diagnosis and follow-up. Vertebral height measurements
can objectively be made using plain-film X-rays by using several methods such as height loss
together with area reduction, particularly when looking at vertical deformity in T4-L4, or by
determining a spinal fracture index that takes into account the number of vertebrae involved.
Involvement of multiple vertebral bodies leads to kyphosis of the thoracic spine, leading to what
is known as dowager's hump.
Page | 19
Figure No : 14. CT scan of the cervical spine
1.7.2. Dual-energy X-ray
Dual-energy X-ray absorptiometry (DEXA scan) is considered the gold standard for the
diagnosis of osteoporosis. Osteoporosis is diagnosed when the bone mineral density is less than
or equal to 2.5 standard deviations below that of a young (30–40-year-old), healthy adult women
reference population. This is translated as a T-score. But because bone density decreases with
age, more people become osteoporotic with increasing age. The World Health Organization has
established the following diagnostic guidelines:
Table No : 01. Diagnostic guidelines of osteoporotic
Category T-score range % young women
Normal T-score ≥ − 1.0 85%
Osteopenia − 2.5 < T-score < − 1.0 14%
Osteoporosis T-score ≤ − 2.5 0.6%
Severe osteoporosis T-score ≤ −2.5 with fragility fracture
Page | 20
The International Society for Clinical Densitometry takes the position that a diagnosis of
osteoporosis in men under 50 years of age should not be made on the basis of densitometric
criteria alone. It also states, for premenopausal women, Z-scores (comparison with age group
rather than peak bone mass) rather than T-scores should be used, and the diagnosis of
osteoporosis in such women also should not be made on the basis of densitometric criteria alone.
Figure No : 15. DEXA scan of bone density
1.7.3. Biomarkers
Chemical biomarkers are a useful tool in detecting bone degradation. The enzyme cathepsin
K breaks down type-I collagen, an important constituent in bones. Prepared antibodies can
recognize the resulting fragment, called a neoepitope, as a way to diagnose osteoporosis.
Increased urinary excretion of C-telopeptides, a type-I collagen breakdown product, also serves
as a biomarker for osteoporosis.
Page | 21
Table No: 02. Comparison of bone pathology
Alkaline Parathyroid
Calcium Phosphate Comments
Condition phosphatase hormone
variable
abnormal
(depending on
Paget's disease of bone unaffected unaffected unaffected bone
stage of
architecture
disease)
thick dense
bones also
Osteopetrosis unaffected unaffected elevated unaffected
known as
marble bone
decreased
Osteopenia unaffected unaffected normal unaffected
bone mass
Osteomalacia and rickets decreased decreased elevated elevated soft bones
brown
Osteitis fibrosa cystica elevated decreased elevated elevated tumors
Osteomalacia and rickets decreased decreased elevated elevated soft bones
decreased
Osteopenia unaffected unaffected normal unaffected
bone mass
thick dense
bones also
Osteopetrosis unaffected unaffected elevated unaffected
known as
marble bone
variable
abnormal
(depending on
Paget's disease of bone unaffected unaffected unaffected bone
stage of
architecture
disease)
Page | 22
1.7.4. Other measuring tools
Quantitative computed tomography (QCT) differs from DXA in that it gives separate estimates
of BMD for trabecular and cortical bone and reports precise volumetric mineral density in
mg/cm3 rather than BMD's relative Z-score. Among QCT's advantages: it can be performed at
axial and peripheral sites, can be calculated from existing CT scans without a separate radiation
dose, is sensitive to change over time, can analyze a region of any size or shape, excludes
irrelevant tissue such as fat, muscle, and air, and does not require knowledge of the patient's
subpopulation in order to create a clinical score (e.g. the Z-score of all females of a certain age).
Among QCT's disadvantages: it requires a high radiation dose compared to DXA, CT scanners
are large and expensive, and because its practice has been less standardized than BMD, its results
are more operator-dependent. Peripheral QCT has been introduced to improve upon the
limitations of DXA and QCT.
Quantitative ultrasound has many advantages in assessing osteoporosis. The modality is small,
no ionizing radiation is involved, measurements can be made quickly and easily, and the cost of
the device is low compared with DXA and QCT devices. The calcaneus is the most common
skeletal site for quantitative ultrasound assessment because it has a high percentage of trabecular
bone that is replaced more often than cortical bone, providing early evidence of metabolic
change. Also, the calcaneus is fairly flat and parallel, reducing repositioning errors. The method
can be applied to children, neonates, and preterm infants, just as well as to adults. Some
ultrasound devices can be used on the tibia.
Page | 23
Figure No: 16. Quantitative computed tomography of the lumbar spine and the hip Source
1.7.5. Screening
The U.S. Preventive Services Task Force (USPSTF) recommend that all women 65 years of age
or older be screened by bone densitometry. Additionally they recommend screening younger
women with risk factors. There is insufficient evidence to make recommendations about the
intervals for repeated screening and the appropriate age to stop screening.
In men the harm versus benefit of screening for osteoporosis is unknown. Prescrire states that the
need to test for osteoporosis in those who have not had a previous bone fracture is unclear. The
International Society for Clinical Densitometry suggest BMD testing for men 70 or older, or
those who are indicated for risk equal to that of a 70-year-old. A number of tools exist to help
determine who is reasonable to test.
Page | 24
1.8. Treatment
A number of effective medications are approved for the prevention and treatment of
osteoporosis. These medications must be tailored to a person's specific needs and used in
conjugation with recommended lifestyle changes.
 Bisphosphonates: Bisphosphonates (BP) are potent inhibitors of bone resorption that
inhibit the activity of osteoclasts. All approved bisphosphonates have been shown to
reduce vertebral fracture risk and increase BMD, whereas some have demonstrated
reductions in non-vertebral and hip fracture risk as well. Bisphosphponates bind to bone
mineral, and consequently have a long skeletal retention. Examples include alendronate,
risedronate, zoledronic acid etc.
 Calcitonin: This 32-amino-acid peptide secreted by the C-cells of the thyroid inhibits
activity of osteoclasts, slows bone resorption, but induces only a mild increase in bone
mineral density BMD. Nasal salmon calcitonin decreased the incidence of vertebral
fractures by 33 % in older osteoporotic women, most of whom had prevalent vertebral
fractures. Salmon calcitonin appears to reduce the pain associated with acute vertebral
fractures.
 Denosumab: Denosumab prevents the binding of receptor activator of nuclear factorkB
ligand (RANKL) to receptor activator of nuclear factor-kB (RANK) on the cells of the
osteoclastic lineage. RANKL binds to RANK and stimulates osteoclast differentiation,
activation and survival. It inhibits bone resorption strongly and rapidly, e.g. serum CTX-I
decreases by more than 80 % one week after denosumab injection.
 Selective Estrogen Receptor Modulators (SERM): Selective estrogen receptor
modulators (SERM) have the ability to bind to oestrogen receptors throughout the body
and act as estrogen agonists or antagonists depending upon the target organ. Examples
are raloxifene, bazedoxifene etc.
 Strontium ranelate: Strontium ranelate slightly inhibits bone resorption, slightly
stimulates bone formation and progressively dose-dependently increases BMD, decreases
the incidence of vertebral fractures.
 Teriparatide: Recombinant human parathyroid hormone teriparatide and recombinant
human intact parathyroid hormone are effective stimulators of bone formation. They
stimulate bone remodeling at the bone remodeling unit and bone modeling on quiescent
Page | 25
bone surfaces. They induce a prompt increase in bone formation followed by a slower
increase in bone resorption.
 Hormone replacement therapy (HRT): Hormone replacement therapy (HRT) may
consist of oestrogens alone or in combination with progestin. HRT slows bone turnover
and increases bone mineral density (BMD) at all skeletal sites in early and late
postmenopausal women.
 Vertebroplasty and Kyphoplasty: Vertebroplasty and kyphoplasty are minimally
invasive surgical procedures which aim to relieve symptoms associated with vertebral
compression fractures (International Osteoporosis Foundation, 2015).
1.9. Prevention
Genetic factors play a significant role in determining whether an individual is at heightened risk
of osteoporosis. However, lifestyle factors such as diet and physical activity also influence bone
development in youth and the rate of bone loss later in life. After your mid - 20s, bone thinning
is a natural process and cannot be completely stopped. The thicker your bones, the less likely
they are to become thin enough to break. Young women in particular need to be aware of their
osteoporosis risk and take steps to slow its progress and prevent fractures. It can be prevented
with proper calcium, vitamin D, nutrition intake and exercise.
Children and adolescents should:
 Ensure a nutritious diet with adequate calcium intake

 Avoid protein malnutrition and under-nutrition
 Maintain an adequate supply of vitamin D
 Participate in regular physical activity
 Avoid the effects of second-hand smoking
It’s estimated a 10% increase of peak bone mass in children reduces the risk of an osteoporotic
fracture during adult life by 50%. Bone mass acquired during youth is an important determinant
of the risk of osteoporotic fracture during later life. The higher the peak bone mass, the lower the
risk of osteoporosis. Once peak bone mass has been reached, it is maintained by remodelling.
This is a continuous process in which old bone is removed (resorption) and new bone is created
(formation). The renewal of bone is responsible for bone strength throughout life. During
childhood and the beginning of adulthood, bone formation is more important than bone
Page | 26
resorption. Later in life, however, the rate of bone resorption is greater than the rate of bone
formation and results in net bone loss. Any factor which causes a higher rate of bone remodelling
will ultimately lead to a more rapid loss of bone mass and more fragile bones. The nutritional
and lifestyle advice for building strong bones are applicable for both young and adult.
Adults should:
 Ensure a nutritious diet and adequate calcium intake
 Avoid under-nutrition, particularly the effects of severe weight-loss diets and eating
disorders
 Maintain an adequate supply of vitamin D
 Participate in regular weight-bearing activity
 Avoid smoking and second-hand smoking
 Avoid heavy drinking
1.9.1. Calcium
Recommended daily calcium allowances for populations vary between countries. The IOM 2010
(Institute of Medicine of the US National Academy of Sciences) recommendations are as
follows:
Table No : 03. Dietary Recommended Intake of calcium (International Osteoporosis
Foundation,2015).
Page | 27
Calcium rich foods
Milk and dairy products are the most readily available dietary sources of calcium. Dairy foods
have the additional advantage of being good sources of protein and other micronutrients
important for bone health.
Other sources of calcium include:
 Green vegetables like broccoli, curly kale

 Some fruits such as oranges, apricots and dried figs
 Canned fish with soft, edible bones (the calcium is in the bones) such as sardines,
pilchards and salmon
 Nuts, especially Brazil nuts and almonds
 Calcium-set Tofu
 Some calcium-fortified breads, cereals, fruit juices, soy beverages and several brands of
commercial mineral water also contain significant amounts of calcium. These foods
provide a suitable alternative for people who are lactose-intolerant or vegan.
 Some leafy produce, like spinach and rhubarb, contain 'oxalates', which prevent the
calcium present in these vegetables from being absorbed. However, they do not interfere
with calcium absorption from other calcium-containing foods eaten at the same time. The
same is true of 'phytates' in dried beans, cereal husks and seeds.
Foods to avoid
Caffeine and salt can increase calcium loss from the body and should not be taken in excessive
amounts. Alcohol should also be taken in moderation as it detracts from bone health and is
associated with falls and fractures. No conclusive evidence shows that fizzy soft drinks (e.g. cola
drinks) weaken bones, but here too, it's best not to overdo it - especially as such drinks tend to
'displace' milk in the diets of children and teenagers.
1.9.2. Vitamin D
Vitamin D is essential for the development and maintenance of bone, both for its role in assisting
calcium absorption from food in the intestine, and for ensuring the correct renewal and
mineralization of bone tissue. The type of vitamin D made in the skin is referred to as vitamin D3
(cholecalciferol), whereas the dietary form can be vitamin D3 or a closely related molecule of
Page | 28
plant origin known as vitamin D2 (ergocalciferol). The main source of vitamin D is ultraviolet
ray.
Sources of vitamin D
Vitamin D is made in the skin when it is exposed to ultraviolet B rays; in children and adults
exposure of the hands, face and arms to the sun for 10 to 15 minutes per day is usually ufficient
for most individuals. However, how much vitamin D is produced from sunlight depends on the
time of day, where you live in the world and the color of your skin. Vitamin D can also be
obtained from food, and dietary supplements. Food sources are rather limited, and include oily
fish such as salmon, sardines and mackerel, eggs, liver, and in some countries fortified foods
such as margarine, dairy foods and cereals.
Table No : 04. Dietary Reference Intakes for Vitamin D (International Osteoporosis
Foundation, 2015).
1.9.3. Other nutrition

A healthy diet can help you prevent and manage osteoporosis and related musculoskeletal
disorders by assisting in the production and maintenance of bone. Two of the most important
nutrients are calcium and vitamin D. Calcium is a major building-block of bone tissue (the
skeleton houses 99% of the body’s calcium stores). Vitamin D is key at it assists your body to
absorb calcium, the two go hand in hand.
Protein
Adequate dietary protein is essential for optimal bone mass gain during childhood and
adolescence. It’s also responsible for preserving bone mass with ageing. Lack of protein robs the
muscles of strength, which heightens the risk of falls, and contributes to poor recovery in patients
Page | 29
who have had a fracture. Lean red meat, poultry and fish, as well as eggs and dairy foods, are
excellent sources of animal protein. Vegetable sources of protein include legumes (e.g. lentils,
kidney beans), soya products (e.g. tofu), grains, nuts and seeds.
Fruits and Vegetables
Fruits and vegetables contain an array of vitamins, minerals, antioxidants and alkaline salts some
or all of which can have a beneficial effect on bone. Studies have shown higher fruit and
vegetable consumption is associated with beneficial effects on bone density in elderly men and
women.
B Vitamins and Homocysteine
Some studies suggest high blood levels of the amino acid homocysteine may be linked to lower
bone density and higher risk of hip fracture in the eldery. Vitamins B6 and B12, as well as folic
acid, play a role in changing homocysteine into other amino acids for use by the body, so it is
possible that they might play a protective role in osteoporosis.
Vitamin A
The role of vitamin A in osteoporosis is controversial. Vitamin A is present as a compound
called retinol in foods of animal origin, such as liver and fish liver oils, dairy foods and egg yolk,
green leafy vegetables, and red and yellow colored fruits and vegetables.
Vitamin K
Vitamin K is required for the correct mineralization of bone. Some evidence suggests low
vitamin K levels lead to low bone density and increased risk of fracture in the elderly. Sources
include leafy green vegetables such as lettuce, spinach and cabbage, liver and some fermented
cheeses and soya bean products.
Zinc
This mineral is required for bone tissue renewal and mineralization. Severe deficiency is usually
associated with calorie and protein malnutrition, and contributes to impaired bone growth in
children. Milder degrees of zinc deficiency have been reported in the elderly and could
potentially contribute to poor bone status. Sources of zinc include lean red meat, poultry, whole
grain cereals, pulses and legumes.
1.9.4. Exercise
Exercise plays an important role in building and maintaining bone and muscle strength. It also
helps to reduce falls by improving balance and aids rehabilitation from fractures. Muscles and
Page | 30
bones respond and strengthen when they are 'stressed'. This can be achieved by weight bearing or
impact exercises.
 It builds strong bones in youth. It’s estimated a 10 per cent increase of peak bone mass in
children can reduce the risk of an osteoporotic fracture during adult life by 50 per cent.
 Exercise plays a key role in adults preventing bone loss and maintaining muscle strength.
 It helps prevent weak bones and falls in the elderly. One-third of people over 65 have a
fall each year and the risk of falling increases as age rises.
 People who have suffered fractures can benefit from special exercises and training (under
medical supervision) to improve muscle strength and muscle function for greater mobility
and improved quality of life (International Osteoporosis Foundation, 2015).
Page | 31
Chapter-Two
Method and Material
Page | 32
2.1. Introduction
Osteoporosis, which literally means porous bone, is a disease in which the density and quality of
bone are reduced. As bones become more porous and fragile, the risk of fracture is greatly
increased. The loss of bone occurs silently and progressively. Often there are no symptoms until
the first fracture occurs.
Osteoporosis (OP) is defined as a disease characterized by low bone mass and microarchitectural
deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in
fracture risk.
Bones are living tissue and constantly changing. From the moment of birth until young
adulthood, bones are developing and strengthening. They are most dense in age like early 20s
called peak bone mass. With aging some of the bone cells begin to dissolve bone matrix
(resorption), while new bone cells deposit osteoid (formation). This process is known as
remodeling. For people with osteoporosis, bone loss outpaces the growth of new bone. Bones
become porous, brittle and prone to fracture (International Osteoporesis Foundation, 2015). Due
to its prevalence worldwide, osteoporosis is considered a serious public health concern.
Currently it is estimated that over 200 million people worldwide suffer from this disease.
Approximately 30% of all postmenopausal women have osteoporosis in the United States and in
Europe. At least 40% of these women and 15-30% of men will sustain one or more fragility
fractures in their remaining lifetime. Ageing of populations worldwide will be responsible for a
major increase in the incidence of osteoporosis in postmenopausal women. Wrist fractures are
most likely to occur in women over 65 years old. An increase in ageadjusted incidence in white
women between 45 and 60 years of age has been observed. Then the trend stabilises or slightly
increases. Only 15% of wrist fractures occur in men and this rate does not increase much with
age. (NHMRC, 2010)
Page | 33
2.2. Method
Data sources and study eligibility
The electronic databases EMBASE, HealthStar, International Pharmaceutical Abstracts,
MEDLINE, and PubMed were searched from database development to April 2010 to identify all
English language publications that presents about of osteoporosis and durg induced osteoporosis.
The search terms were targeted government, research institution, professional association, and
osteoporosis foundation websites to try to capture research published as a report and not
accessible through traditional research databases. Abstracts, commentaries, letters, news articles,
and review papers were included. After that review the literature of the osteoporosis and drug
induced osteoporosis. Then correlate the both osteoporosis disease and literature review. The
correlationship of the osteoporosis indicated. I, therefore identified all papers that included about
osteoporosis and drug induced osteoporosis.
Page | 34
Chapter-Three
Literature Review
Page | 35
3.1. Systems pharmacology dissection of action mechanisms of Dipsaci Radix
for osteoporosis.
Zhang W, Xue K, Gao Y, Huai Y, Wang W, Miao Z, Dang K, Jiang S, Qian A.

Life Sci. doi: 10.1016/j.lfs.2019.116820. [Epub ahead of print]
Available link : https://www.ncbi.nlm.nih.gov/pubmed/31476308
Abstract
AIMS:
Osteoporosis (OP) is a systemic metabolic bone disease characterized by bone mass decrease and
microstructural degradation, which may increase the risk of bone fracture and leading to high
morbidity. Dipsaci Radix (DR), one typical traditional Chinese medicine (TCM), which has been
applied in the treatment of OP with good therapeutic effects and few side effects. However, the
underlying molecular mechanisms of DR to treat OP have not been fully elucidated. In this
study, we aim to dissect the molecular mechanism of DR in the treatment of OP.
MATERIALS AND METHODS:

A systems pharmacology approach was employed to comprehensively dissect the action
mechanisms of DR for the treatment of OP.
KEY FINDINGS:
10 compounds were screened out as the potential active ingredients with excellent biological
activity based on in silico ADME (absorption, distribution, metabolism and excretion) prediction
model. Then, 36 key protein targets of 6 compounds were identified by systems drug targeting
model (SysDT) and they were involved in several biological processes, such as osteoclast
differentiation, osteoblast differentiation and anti-inflammation. The target-pathway network
indicated that targets are mainly mapped in multiple signaling pathways, i.e., MAPK, Tumor
necrosis factor (TNF), NF and Toll-like receptor pathways. The in vitro results indicated that the
compounds ursolic acid and beta-sitosterol effectively inhibited the osteoclast differentiation.
SIGNIFICANCE:
These results systematically dissected that DR exhibits the therapeutic effects of OP by the
regulation of immune system-related pathways, which provide novel perspective to drug
development of OP.
Page | 36
3.2. The Effect of Abnormal Iron Metabolism on Osteoporosis.
Che J, Yang J, Zhao B, Zhang G, Wang L, Peng S, Shang P.
Biol Trace Elem Res. doi: 10.1007/s12011-019-01867-4. [Epub ahead of print]
Abstract
Iron is one of the important trace elements in life activities. Abnormal iron metabolism increases
the incidence of many skeletal diseases, especially for osteoporosis. Iron metabolism plays a key
role in the bone homeostasis. Disturbance of iron metabolism not only promotes osteoclast
differentiation and apoptosis of osteoblasts but also inhibits proliferation and differentiation of
osteoblasts, which eventually destroys the balance of bone remodeling. The strength and density
of bone can be weakened by the disordered iron metabolism, which increases the incidence
of osteoporosis. Clinically, compounds or drugs that regulate iron metabolism are used for the
treatment of osteoporosis. The goal of this review summarizes the new progress on the effect of
iron overload or deficiency on osteoporosis and the mechanism of disordered iron metabolism
on osteoporosis. Explaining the relationship of iron metabolism with osteoporosis may provide
ideas for clinical treatment and development of new drugs.
3.3. MiR-128 inhibits the osteogenic differentiation in osteoporosis by down-

regulating SIRT6 expression.
Zhao J, Liu S, Zhang W, Ni L, Hu Z, Sheng Z, Yin B.
Biosci Rep. doi: 10.1042/BSR20191405. [Epub ahead of print]
Abstract
BACKGROUND:
MicroRNAs (miRNAs) are involved in the regulation of osteogenic differentiation and
chondrification in vivo. The purpose of this study was to explore the potential mechanism of
miR-128 in osteoporosis (OP). Methods: Quantitative real-time PCR (qRT-PCR) was used to
Page | 37
determine the expression of miR-128 in femoral neck trabecular bones of OP patients (n = 40)
and non-OP patients (n = 40). C2C12 cells were transfected with miR-128 mimic or inhibitor to
determine the effect of miR-128 on osteoblastic differentiation of C2C12 cells. Bioinformatics
and luciferase reporter genes were used to determine the molecular mechanism of miR-128 in
osteoblastic differentiation of C2C12 cells. Results: The qRT-PCR results showed that the
expression level of miR-128 in bone samples of OP patients was significantly higher than that of
non-OP patients, while miR-128 was significantly down-regulated during the osteogenic
differentiation of C2C12 cells. In addition, the results showed that overexpression of miR-128
significantly inhibited the mRNA and protein expression levels of osteocalcin (OC), alkaline
phosphatase (ALP) and collagen I type-1 (COL1A1) in C2C12 cells, while miR-128 inhibitor
could reverse this effect. Bioinformatics analysis and dual-luciferase reporter assay found that
SIRT6 was a direct target of miR-128. The qRT-PCR and Western Blot results found that miR-
128 significantly down-regulated the mRNA and protein expressions of SIRT6. Furthermore,
silencing SIRT6 significantly inhibited the promoting effect of the miR-128 inhibitor on the
expression of osteoblast markers.
CONCLUSION:
The above results confirmed that miR-128 inhibited osteoblast differentiation in OP by down-
regulating SIRT6 expression, thus accelerating the development of OP.
3.4. Combination denosumab and high dose teriparatide for postmenopausal

osteoporosis (DATA-HD): a randomised, controlled phase 4 trial.
Tsai JN, Lee H, David NL, Eastell R, Leder BZ.
Lancet Diabetes Endocrinol. pii: S2213-8587(19)30255-4. doi: 10.1016/S2213-8587(19)30255-

4. [Epub ahead of print]
Abstract
BACKGROUND:
In the Denosumab and Teriparatide Administration (DATA) study, we showed that denosumab
fully inhibits teriparatide-induced bone resorption while allowing for continued teriparatide-
induced bone formation, resulting in larger increases in hip and spine bone mineral density
Page | 38
(BMD) than with either drug alone. We aimed to assess whether administration of denosumab
with high dose teriparatide would stimulate larger increases in bone mass than those observed in
the DATA study.
METHODS:
DATA-HD was an open-label, randomised, controlled phase 4 trial done at Massachusetts
General Hospital. Eligible women were postmenopausal women (at least 36 months since last
menses or since hysterectomy with a follicle-stimulating hormone concentration of 40 U/L)
with osteoporosis. Participants were randomly assigned (1:1) to receive teriparatide 20gm
(standard dose) or 40gm (high dose) daily via subcutaneous injection for 9 months. At 3 months,
both groups were started on denosumab 60 mg every 6 months via subcutaneous injection for 12
months. Areal BMD (aBMD) was measured at 0, 3, 9, and 15 months. Treatment was given open
label, but outcome assessors were masked. The primary endpoint was percentage change from
baseline in spine areal BMD (aBMD) at 15 months. Women who completed at least one study
visit after baseline were included in the modified intention-to-treat analysis. Safety was assessed
in all randomly assigned participants. This study is registered with ClinicalTrials.gov,
number NCT02176382.
FINDINGS:
Between Oct 15, 2014, and June 10, 2016, 269 women were assessed for eligibility. 76
participants were randomly assigned to 20gm teriparatide (n=39) or 40gm teriparatide (n=37), of
whom 69 completed at least one post-baseline visit. At 15 months, mean spine aBMD had
increased to a significantly greater extent in the 40gm group (17·5% [SD 6·0] increase) than the
20gm group (9·5% [3·2]; difference 8·1%, 95% CI 5·5 to 10·6, p<0·0001). Mean femoral neck
aBMD had also increased to a greater extent in the 40gm group (6·8% [SD 4·1] increase) than
the 20gm group (4·3% [3·7]; difference 2·5%, 0·5 to 4·5, p=0·04), as did mean total hip aBMD
(40gm group, 6·1% [3·4] increase; 20gm group, 3·9% [2·9] increase; difference 2·2%, 0·6 to 3·8,
p<0·0001). 30 (77%) of 39 participants in the 20gm group and 29 (78%) of 37 participants in the
40gm group had an adverse event, and seven (18%) and two (5%) patients had serious adverse
events. The most frequent adverse events were joint pain (15 [38%]), muscle cramp (15 [38%]),
and fatigue (12 [31%]) in the 20gm group and fatigue (14 [38%]), nausea (16 [43%]), and joint
pain (17 [46%]) in the 40gm group. No deaths were reported.
Page | 39
INTERPRETATION:
Combined treatment with teriparatide 40gm and denosumab increases spine and hip BMD more
than standard combination therapy. This large and rapid increase in bone mass suggest that this
high dose regimen might provide a method of restoring skeletal integrity in patients
with osteoporosis.
3.5. Drug-induced osteoporosis/osteomalacia: analysis in the French and

Spanish pharmacovigilance databases.
Dardonville Q, Salguiero E, Rousseau V, Chebane L, Faillie JL, Gautier S, Montastruc

JL, Carvajal A, Bagheri H.
Eur J Clin Pharmacol. doi: 10.1007/s00228-019-02743-9. [Epub ahead of print]
Abstract
INTRODUCTION:
Osteomalacia and osteoporosis are two metabolic bone disorders that increase the risk of fracture
due to several causes. In terms of drugs, apart from corticosteroids, which are known to induce
bone disorders, several other drugs used in chronic disease management have also been linked
with an increased risk of osteoporosis and osteomalacia.
PURPOSE:
The aim of this study was to describe spontaneous reports of drug-induced osteoporosis and
osteomalacia in the French (FPVDB) and Spanish (SPVDB) pharmacovigilance databases.
METHODS:
Data were provided by the FPVDB and SPVDB. All reports of osteoporosis and osteomalacia
recorded from 1985 up to 31 December 2015 inclusive were selected. Taking the time to onset of
bone loss into account, all cases occurring in less than 1 month were excluded.
RESULTS:
A total of 369 reports (44 cases of osteomalacia, 325 cases of osteoporosis) were registered in
the FPVDB and 64 (22 cases of osteomalacia, 42 cases of osteoporosis) in the SPVDB. In
Page | 40
France, the top 5 drugs involved in the onset of osteoporosis were corticosteroids accounting for
approximately half of the reports (n = 170) followed by systemic antiviral (n = 87), antacid (n =
29), antiepileptic (n = 27) and antithrombotic (n = 24) drugs. The 2 main classes of drugs
implicated in osteomalacia were systemic antiretroviral drugs for half of the reports (n = 21) and
antiepileptic drugs (n = 15). In Spain, corticosteroids were involved in 35.7% of reported cases
of osteoporosis (n = 15) followed by systemic antiviral drugs (n = 12). There was no spontaneous
report for antacid drugs. For osteomalacia, the 2 main drug classes were systemic antiretroviral
drugs (n = 18, 81.8%) followed by antiepileptics (n = 2, 9.0%). In both countries, concomitant
administration of systemic corticosteroids with other suspected drugs did not significantly
modify the time to onset of drug-induced osteoporosis.
CONCLUSION:
Despite some differences between the French and Spanish PVDBs, our data consistently show
that bone loss is not only restricted to glucocorticoids but also involves antivirals, antiepileptic
drugs, antacid drugs or antidepressants. Further analysis might prove useful in exploring the
characteristics of drug-induced bone loss on a larger scale.
3.6. Effect of medications on prevention of secondary osteoporotic vertebral

compression fracture, non-vertebral fracture, and discontinuation due to
adverse events: a meta-analysis of randomized controlled trials.
Jin YZ, Lee JH, Xu B, Cho M.
BMC Musculoskelet Disord. doi: 10.1186/s12891-019-2769-8.
Abstract
BACKGROUND:
Bone loss with aging and menopause increases the risk of fragile vertebral fracture, osteoporotic
vertebral compression fracture (OVCF). The fracture causes severe pain, impedes respiratory
Page | 41
function, lower the quality of life, and increases the risk of new fractures and deaths. Various
medications have been prescribed to prevent a secondary fracture, but few study summarized
their effects. Therefore, we investigated their effects on preventing subsequent OVCF via meta-
analyses of randomized controlled trials.
METHODS:
Electronic databases, including MEDLINE, EMBASE, CENTRAL, and Web of Science were
searched for published randomized controlled trials from June 2015 to June 2019. The trials that
recruited participants with at least one OVCF were included. We assessed the risk of bias of
every study, estimated relative risk ratio of secondary OVCF, non-vertebral fracture,
gastrointestinal complaints and discontinuation due to adverse events. Finally, we evaluated the
quality of evidence.
RESULTS:
Forty-one articles were included. Moderate to high quality evidence proved the effectiveness
of zoledronate (Relative Risk, RR: 0.34; 95% CI, 0.17-0.69, p = 0.003), alendronate (RR: 0.54;
95% CI: 0.43-0.68; p < 0.0001), risedronate (RR: 0.61; 95% CI: 0.51-0.73; p < 0.0001),
etidronate (RR, 0.50; 95% CI, 0.29-0.87, p < 0.01), ibandronate (RR: 0.52; 95% CI: 0.38-0.71;
p < 0.0001), parathyroid hormone (RR: 0.31; 95% CI: 0.23-0.41; p < 0.0001), denosumab (RR,
0.41; 95% CI, 0.29-0.57; p < 0.0001) and selective estrogen receptor modulators (Raloxifene,
RR: 0.58; 95% CI: 0.44-0.76; p < 0.0001; Bazedoxifene, RR: 0.66; 95% CI: 0.53-0.82; p =
0.0002) in preventing secondary fractures. Moderate quality evidence proved romosozumab had
better effect than alendronate (Romosozumab vs. alendronate, RR: 0.64; 95% CI: 0.49-0.84; p =
0.001) and high quality evidence proved that teriparatide had better effect than risedronate
(risedronate vs. teriparatide, RR: 1.98; 95% CI: 1.44-2.70; p < 0.0001).
CONCLUSION:
Zoledronate, alendronate, risedronate, etidronate, ibandronate, parathyroid hormone, denosumab

and selective estrogen receptor modulators had significant secondary prevention effects on
OVCF. Moderate quality evidence proved romosozumab had better effect than alendronate. High
Page | 42
quality evidence proved PTH had better effect than risedronate, but with higher risk of adverse
events.
3.7. Long-term outcome of patients with pregnancy and lactation associated

osteoporosis (PLO) with a particular focus on quality of life.
Gehlen M, Lazarescu AD, Hinz C, Schwarz-Eywill M, Pfeifer M, Balasingam S, Maier A.
Clin Rheumatol. doi: 10.1007/s10067-019-04758-0. [Epub ahead of print]
Abstract
BACKGROUND:
Pregnancy and lactation-associated osteoporosis (PLO) is a very rare form of osteoporosis.
Vertebral fractures either occur in the last trimester of pregnancy or after childbirth. Pathogenesis
is still unclear. Until recently, almost no data existed in regards to the quality of life and long-
term clinical outcome of patients with PLO.
OBJECTIVES:
To determine the long-term clinical outcome of patients with pregnancy and lactation-
associated osteoporosis (PLO) with respect to the following factors: pain, quality of life, mental
condition, vertebral fractures, and capacity to work.
METHODS:
In this single-center retrospective study, patients were reviewed for at least 2 years, more than
50% of them were followed up until menopause. Bone density (DXA) and vertebral fractures
were assessed. Standardized questionnaires were used to analyze factors such as quality of life
(Qualeffo-41), anxiety and depression (PHQ-4), and pain (the visual analog scale [VAS]).
Additionally, a questionnaire was designed in order to evaluate and discuss some of the reasons
behind the occurrence of mental distress at the onset of symptoms.
Page | 43
RESULTS:
Our report shows the clinical course of 20 patients with PLO, 11 of them until menopause (on
average 16.3 years after onset of symptoms). When diagnosis was made, 5.4 vertebral fractures
were noticed on average. Three of the 20 patients developed subsequent fractures in the
following years. The diagnosis of PLO was made on average after 3.3 months after the onset of
symptoms. At the beginning of the investigation, physical and mental health of all patients were
poor, but improved within the first 2 years and continued doing so until menopause. The average
time it took to return to employment was 3.3 years.
CONCLUSION:
PLO has a significant impact on pain, mental state, quality of life, and capacity to work.
However, the long-term prognosis is promising. The severe mental distress is presumably related
to several contributing factors in life such as physical integrity and independence, family life,
employment, and financial security. Key Points • PLO has a strong impact on quality of life and
can lead to severe mental distress. • At onset of symptoms, patients with PLO are in very poor
mental and physical condition; however, the long-term outcome after inpatient rehabilitation
seems to be good. • Most patients do not suffer subsequent vertebral fractures until the
menopause.
3.8. Activation of ROS/MAPKs/NF-B/NLRP3 and inhibition of efferocytosis

in osteoclast-mediated diabetic osteoporosis.
An Y, Zhang H, Wang C, Jiao F, Xu H, Wang X, Luan W, Ma F, Ni L, Tang X, Liu M, Guo

W, Yu L.
FASEB J. doi: 10.1096/fj.201802805RR. [Epub ahead of print]
Abstract
Diabetes mellitus (DM) affects bone metabolism and leads to osteoporosis; however, its
pathogenetic mechanisms remain unknown. We found that high glucose (HG) conditions
induced the production of reactive oxygen species (ROS) and the expression of proteins related
Page | 44
to MAPKs [phosphorylated (p)-ERK, p-JNK, and p-p38], NF-B (NF-B, p-IB, and IKK), and
NACHT-LRR-PYD domains-containing protein 3 (NALP3) (NLRP3) [apoptosis-associated
speck-like protein containing a caspase activation and recruitment domain (ASC), caspase-1, IL-
18, IL-1, and NLRP3] in osteoclasts (OCs) in vitro. Further analysis showed that in HG-induced
OCs, ROS is an upstream signal for MAPKs, NF-B, and the NLRP3 inflammasome. Moreover,
MAPKs mediated the activation of NF-B and NLRP3, whereas NF-B up-regulated the NLRP3
inflammasome response. Interestingly, HG inducement enhanced the bone resorption of OCs but
inhibited their efferocytosis, whereas insulin and lipoxin A4 (4) treatment reversed this
phenomenon. In streptozotocin-induced diabetic rats in vivo, the numbers and the bone-
resorption capacity of OCs as well as the serum levels of TRACP-5b were significantly
increased, and the expression of MAPK-, NF-B-, and NLRP3 inflammasome-related proteins in
the proximal tibia were also significantly elevated; however, treatment with insulin and LXA4
reversed this elevation. Together, these results demonstrated that the activation of
ROS/MAPKs/NF-B/NLRP3 and the inhibition of efferocytosis in OCs are the main causes
of osteoporosis in DM.-An, Y., Zhang, H., Wang, C., Jiao, F., Xu, H., Wang, X., Luan, W., Ma,
F., Ni, L., Tang, X., Liu, M., Guo, W., Yu, L. Activation of ROS/MAPKs/NF-B/NLRP3 and
inhibition of efferocytosis in osteoclast-mediated diabetic osteoporosis.
3.9. Exercise or manual physiotherapy compared with a single session of

physiotherapy for osteoporotic vertebral fracture: three-arm PROVE RCT.
Barker KL, Newman M, Stallard N, Leal J, Minns Lowe C, Javaid MK, Noufaily A, Adhikari
A, Hughes T, Smith DJ, Gandhi V, Cooper C, Lamb SE.
Health Technol Assess. doi: 10.3310/hta23440.
Abstract
BACKGROUND:
A total of 25,000 people in the UK have osteoporotic vertebral fracture (OVF). Evidence
suggests that physiotherapy may have an important treatment role.
Page | 45
OBJECTIVE:
The objective was to investigate the clinical effectiveness and cost-effectiveness of two different
physiotherapy programmes for people with OVF compared with a single physiotherapy session.
DESIGN:
This was a prospective, adaptive, multicentre, assessor-blinded randomised controlled trial
(RCT) with nested qualitative and health economic studies.
SETTING:
This trial was based in 21 NHS physiotherapy departments.
PARTICIPANTS:
The participants were people with symptomatic OVF.
INTERVENTIONS:
Seven sessions of either manual outpatient physiotherapy or exercise outpatient physiotherapy
compared with the best practice of a 1-hour single session of physiotherapy (SSPT).
MAIN OUTCOME MEASURES:

Outcomes were measured at 4 and 12 months. The primary outcomes were quality of life and
muscle endurance, which were measured by the disease-specific QUALEFFO-41 (Quality of
Life Questionnaire of the European Foundation for Osteoporosis - 41 items) and timed loaded
standing (TLS) test, respectively. Secondary outcomes were (1) thoracic kyphosis angle, (2)
balance, evaluated via the functional reach test (FRT), and (3) physical function, assessed via the
Short Physical Performance Battery (SPPB), 6-minute walk test (6MWT), Physical Activity
Scale for the Elderly, a health resource use and falls diary, and the EuroQol-5 Dimensions, five-
level version.
RESULTS:
A total of 615 participants were enrolled, with 216, 203 and 196 randomised by a computer-
generated program to exercise therapy, manual therapy and a SSPT, respectively. Baseline data
were available for 613 participants, 531 (86.6%) of whom were women; the mean age of these
participants was 72.14 years (standard deviation 9.09 years). Primary outcome data were
obtained for 69% of participants (429/615) at 12 months: 175 in the exercise therapy arm, 181 in
the manual therapy arm and 173 in the SSPT arm. Interim analysis met the criteria for all arms to
Page | 46
remain in the study. For the primary outcomes at 12 months, there were no significant benefits
over SSPT of exercise [QUALEFFO-41, difference -0.23 points, 95% confidence interval (CI) -
3.20 to 1.59 points; p = 1.000; and TLS test, difference 5.77 seconds, 95% CI -4.85 to 20.46
seconds; p = 0.437] or of manual therapy (QUALEFFO-41, difference 1.35 points, 95% CI -1.76
to 2.93 points; p = 0.744; TLS test, difference 9.69 seconds (95% CI 0.09 to 24.86 seconds; p =
0.335). At 4 months, there were significant gains for both manual therapy and exercise therapy
over SSPT in the TLS test in participants aged <70 years. Exercise therapy was superior to a
SSPT at 4 months in the SPPB, FRT and 6MWT and manual therapy was superior to a SSPT at 4
months in the TLS test and FRT. Neither manual therapy nor exercise therapy was cost-effective
relative to a SSPT using the threshold of £20,000 per quality-adjusted life-year. There were no
treatment-related serious adverse events.
CONCLUSIONS:
This is the largest RCT to date assessing physiotherapy in participants with OVFs. At 1 year,
neither treatment intervention conferred more benefit than a single 1-hour physiotherapy advice
session. The focus of future work should be on the intensity and duration of interventions to
determine if changes to these would demonstrate more sustained effects.
TRIAL REGISTRATION:
Current Controlled Trials ISRCTN49117867.
FUNDING:
This project was funded by the National Institute for Health Research (NIHR) Health
Technology Assessment programme and will be published in full in Health Technology
Assessment; Vol. 23, No. 44. See the NIHR Journals Library website for further project
information.
PLAIN-LANGUAGE-SUMMARY:
Osteoporosis is a condition in which bones lose their strength and are more likely to break. It
affects around 3 million people in the UK. Fractures of the spine are very common in people
with osteoporosis. They can cause a change in body shape, back pain and difficulty with carrying
out daily tasks. A treatment that may help people is physiotherapy. There is evidence that several
different types of physiotherapy, such as exercise or manual (hands-on) therapy, may help. This
was the largest trial of physiotherapy for people with osteoporotic vertebral fracture to date.
Page | 47
Seven sessions of physiotherapy treatment based on either exercise or manual therapy were
compared with a single 1-hour session of individualised advice from a physiotherapist. The
outcome of these treatments was assessed using recognised measures of quality of life, back
muscle strength, pain, function and activity at 4 months and 1 year after treatment. How safe the
treatments were and whether or not they had any impact on falls or the costs of health and social
care were also examined. Interviews were conducted with some of the participants in the trial to
seek their opinion about the treatment that they had received. The results show that the
participants tolerated all the treatments well, with no significant safety issues, and perceived
treatment to be beneficial. The study did not find significant differences between the three
treatments in terms of clinical effectiveness or cost-effectiveness at 1 year, although there were
benefits in some areas at 4 months.
3.10. A novel device to prevent osteoporosis by promoting bone metabolism

using a newly developed double-loading stimulation with vibration and
shaking.
Yao R, Nishii K, Kito T, Teranishi T, Sugiyama T, Sakai K, Matsubara M, Yamada K.
Okajimas Folia Anat Jpn. doi: 10.2535/ofaj.96.13.
Abstract
In Japan, 13 million people have osteoporosis, including approximately 9 hundred thousand
people who are bedridden owing to bone fractures from falls. Preventing osteoporosis is
considered to be an important and effective way of preventing fall-related fractures. Thus, we
developed a novel method of locomotor stimulation and analyzed its effectiveness in mice.
Specifically, we created a double-loading device that combines vibration and shaking
stimulation. The device was used to continuously stimulate ovariectomy-induced decreased bone
density mouse models 30 minutes daily for 10 weeks. We then collected femur samples, created
undecalcified tissue slices, calculated parameters using bone histomorphomtry, and conducted
comparative testing. BS/TV (bone surface/tissue volume), N.Oc/ES (osteoclast number/eroded
surface), Oc.S/ES (osteoclast osteoid surface/eroded surface), Omt (osteoid maturation time),
Page | 48
Tb.N (trabecular number), Mlt (mineralization lag time) < (p < 0.01), N.Ob (osteoblast number),
N.Ob/TV (osteoblast number/tissue volume), sLS (single labeled suface), N.Mu.Oc/ES
(multinucle osteoclast number/eroded surface), and N.Mo.Oc/ES (mononucle osteoclast
number/eroded surface) (p < 0.05) were significantly higher in the stimulation group than in the
non-stimulation group. In addition, BS/BV (bone surface/bone volume), Tb.Sp (trabecular
separation), MAR (mineral apposition rate), Aj.Ar (adjusted apposition rate) (p < 0.01), ES
(eroded surface ), ES/BS (eroded surface/bone surface), and BRs.R (bone resorption rate) (p <
0.05) were significantly lower in the stimulation group than in the non-stimulation group. These
results suggest that stimulation activated osteoblasts and osteoclasts, thereby leading to highly
active bone remodeling. We anticipate that bone mineralization will subsequently occur,
suggesting that this stimulation technique is effective in preventing osteoporosis by alleviating
sudden bone density loss.
Page | 49
Chapter-Four
Results and Discussion
Page | 50
4.1. Drug Induced Osteoporosis
Bone is a metabolically active tissue that undergoes remodeling throughout life, with roughly 5%
remodeled at any time. Over several weeks, a bone remodeling unit, termed basic multicellular
unit (BMU), will develop that incorporates several cell types, including osteoclasts, osteoblasts,
and osteocytes. Bone remodeling is held in check by osteocyte secreted sclerostin, a Wnt
inhibitor that prevents bone formation by osteoblasts, until osteocytes sense bone stress or
microdamage and undergo apoptosis. The loss of sclerostin and alterations in other secreted
cytokines and chemotactic factors promote BMU’s formation. Osteoclasts are recruited into the
area by gradients of macrophage colony-stimulating factor and receptor activator of nuclear
factor B ligand (RANKL). Osteoclasts attach and excavate bone over several weeks prior to
apoptosing. RANKL is antagonized by osteoprotegrin (OPG), a decoy RANK receptor, and
alterations in the ratio of RANKL to OPG contribute to excessive bone remodeling. Following
osteoclast apoptosis, pre-osteoblasts are recruited to the eroded surface and differentiate into
osteoblasts. Mature osteoblasts secrete unmineralized bone called osteoid that subsequently
becomes mineralized over several months. Mineralization of osteoid requires adequate vitamin D
and calcium as well as osteoblast-secreted osteocalcin. The coupling of osteoclast resorption to
osteoblast bone formation is critical to preserve bone homeostasis. Postmenopausal osteoporosis
is one example of uncoupling with increased osteoclast activity compared with osteoblastic
activity. Many drugs alter the coupled cellular responses of osteoclasts and osteoblasts, leading
to clinically evident osteopenia or osteoporosis as follow :
Table No: 05. Commonly prescribed medications that have harmful effects on bone
homeostasis leading to decreases in bone mineral density and increases in fractures.
Drug class Mechanism Reversibility Screening Management Alternate

of action on medication recommendation recommendation medication
discontinuation
Glucocorticoids (GC) Decreased bone Fracture risk Fracture risk analysis Calcium and vitamin D Limit dose and
formation and decreases to with DXA or FRAX supplementation duration of GC
increased bone baseline within 2 Monitor vitamin D Bisphosphonate or Use alternative
resorption years and calcium levels teriparatide according to immunosuppressive
fracture risk agents according to
DXA scan every 2 years underling disease
condition
Proton pump Unknown but Fracture risk No recommendation Calcium and vitamin D H2 blockers
inhibitors (PPIs) maybe due to reverses within 1 supplementationIf possible,
decreased year avoid PPI use with
intestinal bisphosphonates
Page | 51
absorption of
calcium
Antiepileptic drugs Uncertain but Unknown Fracture risk analysis Calcium and increased Newer agents like
(AEDS) may include with DXA or FRAX vitamin D levetiracetam
inactivation of Monitor vitamin D supplementation:nonenzyme-
vitamin D and calcium levels inducing AEDs give 1000–
every 6–12 months 1200 IU vitamin D and for
enzyme-inducing AEDs give
2000-4000 IU vitamin D
daily
Bisphosphonates in
postmenopausal women and
men >50 years
Medroxyprogesterone Reduced Partial to full DXA scan Calcium and vitamin D Oral hormonal
acetate (MPA) estrogen level recovery of bone controversial in this supplementation contraceptives, low-
leading to loss at spine and hip premenopausal Limit therapy to 2–3 years dose estrogen
increased bone population No data on bisphosphonates replacement with
resorption Monitor vitamin D prophylaxis and is currently depot MPA, other
and calcium levels not recommended birth control
methods
Aromatase Inhibitors Reduced Unknown Fracture risk analysis Calcium and vitamin D Not applicable
estrogen with DXA or FRAX supplementation
production Monitor vitamin D Bisphosphonates for
leading to and calcium levels moderate- to high-risk
increased bone patients
resorption Denosumab as alternative
DXA scan every 2 years
while on treatment
GnRH agonists Prevent the May be reversed in Fracture risk analysis Bisphosphonates, Second line:
production of 2 years depending with DXA or FRAX denosumab,raloxifene, or androgen receptor
LH and FSH on dose and Monitor vitamin D toremifene for moderate- to blockers in men
thereby duration of therapy and calcium levels high-risk patents without bone
decreasing DXA scan every 2 years metastasis
testosterone and while on treatment
estradiol leading
to increased
bone resorption
Serotonin selective Uncertain Probable Fracture risk analysis Calcium and vitamin D Alternative classes
reuptake inhibitors with DXA or FRAX supplementation of antidepressants
for patients with other
osteoporosis risk
factors
Monitor vitamin D
and calcium levels
Thiazolidinediones Decreased bone Unknown FRAX for patients Avoid in established Metformin,
formation with other osteoporosis sulfonylureas,
osteoporosis risk No data for prevention insulin
factors
Monitor vitamin D
and calcium levels
Calcineurininhibitors Excessive Unknown DXA/FRAX analysis Calcium and vitamin D
osteoclasts and prior to kidney supplementation
bone resorption transplant DXA prior to and every 2
with Monitor vitamin D years post organ transplant
glucocorticoids and calcium levels Bisphosphonates for T score
< − 2.0
Heparin Osteoblast Near complete No published No published Fondaparinux if
inhibition with reversal of BMD recommendations recommendations applicable
decreased bone
formation;
increased bone
resorption
Warfarin Decreases bone Unknown No published No published
mineralization recommendations recommendations
Page | 52
4.1.1. Glucocorticoids (GCs)
4.1.1.1. Results using of Glucocorticoids (GCs)
GCs are used to treat a wide variety of diseases, including autoimmune, inflammatory,
dermatological, respiratory diseases, malignancies, and solid organ transplants. Around 30–50%
of patients receiving GCs develop fractures. GCs at doses as low as prednisone 3–10 mg are
associated with fractures. GCs have a wide variety of direct and indirect effects on bone, which
were recently reviewed in detail by Henneickle and colleagues [Henneicke et al. 2014]. In the
early phase, there are multiple direct effects on bone cells, including osteocytes, osteoblasts, and
osteoclasts. GC stimulation of osteoclasts induces prolonged survival allowing excessive bone
resorption primarily in the trabecular rich regions of the spine. GCs also induce osteocyte
apoptosis contributing to early fracture risk occurring before the bone mineral density (BMD) is
reduced. Finally, GCs reduce the recruitment of osteoblast precursors leading to decreased
osteoblast differentiation and function, resulting in decreased bone formation. Indirect effects
contributing to GC-induced bone loss include decreases in calcium resorption, suppression of
growth hormone, alteration in sex hormones, and changes in parathyroid pulsatility. Importantly,
fracture risk increases even before declines in BMD appear, and fractures occur at higher BMD
than seen in postmenopausal osteoporosis.
Data suggest that the daily dose of GC predicts fracture more than the cumulative dose. While
doses over 7.5 mg of prednisone have a fivefold higher risk of spine and hip fractures, even daily
2.5 mg doses are associated with an increased risk of spine fractures. Highlighting the sensitivity
of vertebrae to GCs, prednisone 10 mg daily for more than 90 days leads to a 17-fold increase in
vertebral fractures compared with a sevenfold increase in hip fractures. Although all patients are
at risk for GC-induced bone loss, postmenopausal women and older men are at highest risk when
doses are greater than 20 mg daily. Additional factors that independently increase the risk of
developing GC-induced fractures include low body mass, smoking, parental hip fracture, more
than three alcoholic drinks a day, and intravenous pulse steroids.
4.1.1.2. Discussion about Glucocorticoids (GCs)
Bisphosphonates, oral or intravenous, are effective at preventing GC-induced BMD decline.

Decisions to prevent or treat GC-induced bone loss are currently based on a varying set of
Page | 53
guidelines that vary by agency and country. Because fracture risk increases before changes in
BMD are detected, the measurement of BMD has limited predictive value in GC-induced
osteoporosis. FRAX (World Health Organization Collaborating Centre for Metabolic Bone
Diseases, University of Sheffield, UK) analysis may underestimate the risk of GC-induced
fracture because it assesses the average dose and not the individual or cumulative doses. Despite
these limitations, there is consensus in the guidelines to recommend a baseline BMD
measurement or FRAX analysis before the initiation of GC. Vitamin D, calcium, renal and
hepatic panels are additional studies recommended at baseline and before the decision to prevent
or treat GC-induced bone loss. GC-induced bone loss may be mitigated by minimizing the
steroid dose in addition to concurrent treatment with supplemented calcium, vitamin D, and
bisphosphonates or teriparatide.
Bisphosphonates are currently the standard of care for prevention and treatment of GC-induced
bone loss. Oral or intravenous bisphosphonates are effective at preventing reductions in BMD
and in some cases vertebral fractures induced by GCs. Yearly intravenous zoledronic acid may
provide more rapid protection from GC-induced bone loss and might be appropriate for patients
on high doses of GCs or already on GCs for more than 90days. For patients intolerant of
bisphosphonates or at very high risk of fracture, teriparatide is an alternative. Compared with
alendronate, in an 18-month randomized, double-blinded, head-to-head trial, teriparatide
increased spinal BMD faster and to a greater extent than bisphosphonates and also reduced
vertebral fractures (0.6% versus 6.1%, p = 0.004). The anabolic effect of teriparatide is more
effective at counteracting the deleterious effects of GCs and prevents osteoblast and osteocyte
apoptosis resulting in reduced fracture risk. Although not approved by the US Food and Drug
Administration for the treatment of GC-induced osteoporosis, denosumab improves the BMD of
patients with rheumatoid arthritis receiving oral GCs (average dose 15 mg/day) and may be
considered an alternative therapy for appropriate patients.
There are many guidelines published concerning prevention and treatment of GC-induced bone
loss, including the American College of Rheumatology (ACR), the International Osteoporosis
Foundation (IOF), and the Belgian Bone Club (BBC). All guidelines recommend calcium and
vitamin D supplementation. The BBC has the most general guidelines and recommends
bisphosphonates for any adult taking at least 7.5 mg of prednisone daily for at least 3 months.
Page | 54
The IOF is more conservative and recommends treatment for postmenopausal women and men
aged 70 years or over, or with a previous fragility fracture, taking at least 7.5 mg of prednisolone
daily for at least 3 months. Based on FRAX analysis, younger patients with risk of hip fracture
greater than 3% or risk of a major fracture greater than 20%, bisphosphonate therapy should be
offered. Premenopausal women and younger men under 50 years, who have had a fragility
fracture, should be offered preventive treatment.
ACR guidelines are the most aggressive in terms of treating patients to prevent GC-induced bone
loss. It recommends several tiers of therapy based on FRAX analysis and risk factors. For
postmenopausal women and men above age 50 considered low risk (<10% risk of major
fracture), oral bisphosphonates are recommended for prednisone dosing of at least 7.5 mg/day.
For patients at moderate risk (10–20% risk of major fracture) in that age group, oral
bisphosphonates are recommended for any dose of GCs, and intravenous zoledronic acid can be
considered for prednisone dosing at least 7.5 mg/day. For higher risk (>20% risk of major
fracture or T score ≤ − 2.5) postmenopausal women and men older than 50 years, it is
recommended they take a bisphosphonate when starting any dose of GC. Patients in this high-
risk group taking at least 5 mg/day of prednisone for up to 1 month or any GC dose for more
than 1 month may alternatively be treated with teriparatide. Premenopausal women who do not
have child-bearing potential, and men under 50 years old may be offered oral bisphosphonate
therapy for prednisone doses above 5 mg/day. If the GC dose is at least 7.5 mg/ day, then
intravenous zoledronic acid or teriparatide may be considered. For women of childbearing
potential who are at high risk and are taking at least 7.5 mg/day of prednisone for at least 3
months, bisphosphonates or teriparatide are options. However, there are inadequate data about
the risk of bisphosphonates and teriparatide on fetal skeletons in child-bearing women and these
agents should be used with caution. After discontinuation of GCs, fracture risk gradually
declines to baseline over a year or two.
4.1.2. Proton Pump Inhibitors (PPIs)
4.1.2.1. Results using of Proton Pump Inhibitors (PPIs)
PPIs have been widely used since their introduction in the late 1980s. Several large observational
studies suggest that PPI use is associated with a modest increase in osteoporotic fracture risk.
Page | 55
Based on these and two other studies, the US Food and Drug Administration revised labeling for
PPIs in May 2010 to include information about the potential risk of hip, spinal, or radial
fractures.
The mechanism by which PPIs increase fracture risk is not known. There is considerable
speculation that PPIs, by suppressing acid secretion, decrease intestinal absorption of calcium,
leading to increases in bone resorption and osteoporosis. Studies evaluating PPI use and BMD
have found no clear association, suggesting that other properties of bone metabolism or bone
strength are altered with PPI exposure.
Many studies have evaluated the association of PPI use and fracture. Although some studies have
not shown significant effects, many studies evaluating PPI use for more than 1 year have
consistently demonstrated an increased risk of hip fracture (20–62%) and an increased risk of
vertebral fracture (40–60%). In some but not all studies, a duration effect has been seen. Short-
term PPI use is not associated with an increased fracture risk, whereas long-term use for over 1
year increases the odds ratio (OR) to around 1.44, and with more than 7 years of exposure, the
OR increases to 4.55. Thus, fracture risk is dependent on duration of therapy. PPI dose effects
are difficult to quantitatively analyze because of incompatible definitions of doses among the
studies; however, several studies have shown that fracture risk is increased when high doses are
given compared with lower doses. However, a recent meta-analysis found an association of hip
fracture with both high- and low-dose PPI exposure. Another meta-analysis covering over a
million patients, found PPI, but not histamine-2 receptor antagonist (H2 blocker) exposure to be
associated with fractures of the spine and hip.
4.1.2.2. Discussion about Proton Pump Inhibitors (PPIs)
Fortunately, fracture risk is reduced when PPIs are discontinued. No formal studies have been
published prospectively examining the effect of bisphosphonates on PPI-induced fracture risk.
However, several studies suggest that patients on bisphosphonates who also take PPIs have a
further increased risk of fracture. In a Korean population-based study of 24,710 cases and 98,642
controls all over 65 years of age, the OR for hip fracture related to PPI use was 1.34 [95%
confidence interval (CI) 1.24–144] but was increased to 1.7 (95% CI 1.31–2.23) in patients
taking bisphosphonates and PPIs. The increased risk of hip fracture in PPI and bisposphonate
Page | 56
users was present even when adjusted for multiple medications, such as GCs, warfarin,
antiepileptic drugs (AEDs), antidepressants and others, as well as medical conditions known to
be associated with secondary osteoporosis. Higher cumulative doses of PPIs (>30 mg) given in
association with a bisphosphonate led to higher risk of hip fracture. Another population-based
cohort study examined the predictors for fractures while taking bisphosphonates for more than 6
months in a Spanish cohort of 5 million. They found that PPI use was associated with fractures in
bisphosphonate users with an OR of 1.22 (95% CI 1.02–1.46). Based on these data, H2 blockers
should be considered when possible in patients already taking a bisphosphonate. If PPIs are
indicated, then the shortest duration should be considered and the need for continued PPI use
assessed frequently. Patients on PPIs should also be on calcium and vitamin D supplementation.
4.1.3. Antiepileptic Drugs
4.1.3.1. Results using of Antiepileptic Drugs
In addition to epilepsy, which affects roughly 50 million people worldwide, AEDs are used for
the treatment of migraine headaches, psychiatric disorders, chronic pain, and neuropathy. In
epilepsy, AEDs are associated with reductions in bone density in postmenopausal women and
men older than 65 years. Unfortunately, the adverse effects of AEDs on bone metabolism,
especially phenytoin, are also seen in young patients.
Several theories exist concerning the mechanisms of AED-induced bone loss. The cytochrome
P450 enzyme-inducing AEDs, such as phenytoin, phenobarbital, and carbamazepine, accelerate
inactivation of vitamin D which decreases calcium uptake, drives secondary
hyperparathyroidism and accelerates bone loss. Animal studies suggest a direct inhibitory effect
of phenytoin on osteoblast proliferation and decreases in carboxylated osteocalcin, leading to
poor bone mineralization. It is unclear how nonenzyme-inducing AEDs reduce BMD and
increase fractures. However, valproic acid has been associated with fractures due to the
development of hypophosphatemia secondary to Fanconi syndrome.
All AEDs, both enzyme inducers (phenytoin, phenobarbital, carbamazepine) and enzyme
noninducers, such as valproate, are associated with accelerated bone loss and subsequent
increased risk of osteoporotic fracture. A meta-analysis found AED therapy to be associated with
increased risk of fracture, with the relative risk (RR) of 2.2 (95% CI 1.9–2.5). The fracture risk is
Page | 57
dependent on the duration and cumulative dose of AEDs. A recent retrospective study evaluated
nearly 16,000 patients over 50 years of age using AEDs for epilepsy and nonepilepsy indications.
Use of carbamazepine, clonazepam, gabapentin, phenobarbital, and phenytoin were associated
with a significant increase in nontraumatic fractures, while valproate was not. Newer AEDs,
including topiramate and lamotrigine, were also associated with increased fractures. Another
meta-analysis that included 22 studies found a significant increase in fractures for both enzyme-
inducing and nonenzyme-inducing AEDs. In this study, the highest risk of fractures occurred
with exposures to phenobarbital, phenytoin, and topiramate; while valproic acid, gabapentin,
lamotrigine, and carbamazepine had nonsignificant effects on fracture risk. However, in other
studies, gabapentin has been shown to increase bone loss and fracture risk. Levetiracetam has not
been associated with increases in biochemical markers of bone turnover or decreases in BMD
after 1 year of treatment, suggesting that it may not have the significant adverse bone health
problems that older agents carry. However, long-term studies with these newer agents are needed
to assess fracture risk. Thus most studies have concluded that AEDs are associated with a
moderate to severe risk of fractures with prolonged use.
4.1.3.2. Discussion about Antiepileptic Drugs
Evidence-based strategies for prevention, screening, monitoring, and treating bone loss and
osteoporosis associated with AEDs are limited. Routine evaluation of 25-hydroxy vitamin D
before treatment and every 6–12 months of AED therapy is recommended to ensure adequate
vitamin D levels. Patients on nonenzyme-inducing AEDs generally require 1000–1200 IU/day of
vitamin D while those on enzyme-inducing AEDs need 2000–4000 IU/ day to maintain adequate
vitamin D levels. Patients should also receive adequate calcium supplementation. When safe to
do so, patients with epilepsy should be encouraged to actively ambulate and participate in regular
weight-bearing exercises as tolerated.
Until further evidence from additional randomized trials is available, recommendations are that
patients on long-term AEDs should be screened with dual energy X-ray absorptiometry (DXA)
or FRAX analysis. Postmenopausal women and men over 50 years of age with osteoporosis or
osteopenia and a 10-year probability of hip fracture greater than 3% or major fracture greater
than 20% should be treated as per the guidelines of the National Osteoporosis Foundation. A
recent prospective randomized trial evaluated the effects of risedronate 35 mg daily with vitamin
Page | 58
D and calcium in men with epilepsy taking chronic AEDs. This study found bisphosphonate
therapy superior to vitamin D and calcium alone in improving BMD and preventing fractures in
this epileptic population. Similarly, bisphosphonates with calcium and vitamin D
supplementation improves BMD in children with cerebral palsy on chronic AED therapy. Larger
randomized studies are needed to validate the prophylactic use of bisphosphonates in AED users,
especially in younger patients. Careful review of risks and benefits should occur with women of
child-bearing age who are on AEDs and considering bisphosphonates.
4.1.4. Medroxyprogesterone Acetate (MPA)
4.1.4.1. Results using of Medroxyprogesterone Acetate (MPA)
Hormonal contraceptives are among the most effective and most widely used contraceptives.
While oral hormone contraception is not associated with bone loss, MPA, which is widely used
for the treatment of endometriosis and as a contraceptive agent, is associated with bone loss.
Depot MPA (DMPA), given intramuscular or subcutaneously every 3 months, inhibits
gonadotropin secretion and suppresses ovulation as well as estrogen production. Due to the
reduction in estrogen, DMPA induces bone loss similar to pregnancy, with a decrease of 2–8% in
BMD.
4.1.4.2. Discussion about Medroxyprogesterone Acetate (MPA)
Bone loss appears to decline rapidly in the first 2 years of treatment followed by a plateau. Most
studies have shown that DMPA-induced bone loss is reversible, with improvement occurring
quicker in the spine than the hip. Several studies have shown a slight increase in fracture risk
associated with DMPA. This risk occurs in patients under 30 years of age as well as those over
30, and appears to be highest after 2–3 years of treatment. However, women who chose DMPA
may have baseline characteristics that place them at higher risk for traumatic fractures, including
smoking, alcohol use, and exercise patterns. A recent retrospective study confirmed this finding
and showed that incident fracture rates of DMPA users was higher than never users both prior to
initiation of DMPA and after initiation of DMPA. Importantly, the fracture rate ratios (prior to
DMPA, 1.28, and post DMPA, 1.23) did not significantly increase as a result of DMPA use.
More data from prospective long-term studies are needed to fully address the impact of DMPA
exposure on fracture risk.
Page | 59
The role of screening bone health with DXA in DMPA users is controversial. Guidelines from
the American College of Obstetrics and Gynecology, the Society for Adolescent Health and
Medicine, and the World Health Organization do not recommend routine DXA evaluation for
premenopausal women using DPMA. All DMPA users should have vitamin D levels checked
and calcium and vitamin D supplements given. Patients should be encouraged to exercise, stop
smoking, and limit alcohol intake. Studies have shown that prescribing low-dose estrogen
replacement to DMPA users can prevent bone loss in premenopausal women on DMPA. The use
of bisphosphonates or other agents has not been explored in this patient population and is
currently not recommended.
4.1.5. Aromatase Inhibitors
4.1.5.1. Results using of Aromatase Inhibitors
Aromatase inhibitors (AIs), including letrozole, anastrozole, and exemestane, provide effective
adjuvant hormone therapy for estrogen-receptor-positive breast cancer in postmenopausal
women. AIs inhibit the peripheral conversion of androgens to estrogens, resulting in lower
estrogen levels beyond what is normally achieved in menopause and promote accelerated bone
loss.
4.1.5.2. Discussion about Aromatase Inhibitors
Prevention of AI-induced bone loss with antiresorptive drugs has been well studied. Data from
clinical trials in over 4100 patients support the use of intravenous or oral bisphosphonates and
denosumab to prevent AI-induced bone loss in postmenopausal women with breast cancer.
Compared with risedronate, zoledronic acid (4 mg intravenously every 6 months) is more
effective at preventing AI-induced bone loss and increases disease-free survival in patients with
breast cancer. In several large trials, intravenous zoledronic acid is effective when started
simultaneously with AIs or when delayed after a period of AI therapy.
Current recommendations from most professional groups recommend DXA for all women
beginning AI therapy in addition to adequate calcium and vitamin D supplementation. All groups
recommend beginning a bisphosphonate simultaneously with AI therapy for patients with T
scores less than 2.5 or a history of fragility fracture. The Belgian Bone club recommends
Page | 60
bisphosphonate treatment in patients taking AIs with T scores between − 1.0 and − 2.5. The UK
Expert Group recommends bisphosphonates for women treated with AIs who are over 75 years
old and have one or more risk factor independent of BMD. For younger women with osteopenia,
it recommends starting a bisphosphonate at a T sco re of less than − 2.0. Additionally, the UK
Expert Group recommends bisphosphonates at a T score of less than − 1.0 in younger
premenopausal women receiving ovarian suppression. If patients choose not to start a
bisphosphonate, DXA analysis should be repeated every other year to monitor bone loss.
Denosumab is an alternative prevention and treatment strategy for AI-induced bone loss.
Teriparatide is generally not recommend in patients with cancer receiving AIs if they have had
prior radiation, due to the risk of developing osteosarcomas.
4.1.6. Gonadotropin-releasing hormone agonist and androgen-depriuation therapy
4.1.6.1. Results using of Gonadotropin-releasing hormone agonist and androgen-

depriuation therapy
Gonadotropin-releasing hormone agonists (GnRHs) are used to treat polycystic ovary

syndromes, endometriosis, uterine myomas, breast cancer in premenopausal women, and prostate
cancer. GnRHs inhibit gonadotropins leading to a hypogonadal state that resembles menopause
in women and chemical castration in men. Androgen-deprivation therapy (ADT) provides a
survival benefit to men with invasive or metastatic prostate cancer. GnRH analogs bind to GnRH
receptors in the pituitary and downregulate the gonadotropin-producing cells, limiting luteinizing
hormone and follicle-stimulating hormone secretion. This in turns limits the production of
testosterone and estradiol, leading to chemical castration. As such, GnRH therapy, including
leuprolide, goserelin, triptorelin, and histrelin, lead to decreases in BMD. After ADT is started,
the BMD declines by 2–5% in the first year and the risk of hip and vertebral fractures increases
to 20–50% at 5 years. Patient age, rate of BMD decline, and duration of ADT exposure correlate
with fracture risk.
4.1.6.2. Discussion about Gonadotropin-releasing hormone agonist and androgen-

depriuation therapy
Bisphosphonates can prevent and treat ADT-induced bone loss. However, limited data are
available showing bisphosphonates prevent fractures in patients treated with. Other treatments
Page | 61
that do provide fracture reduction include selective estrogen receptor modulators (SERMs), such
as raloxifene and toremifene and denosumab. Alternatives to ADT include antiandrogens, such
as bicalutamide, flutamide, and nilutamide, in men without bone metastases. These drugs
maintain BMD compared with ADT because they inhibit testosterone binding to androgen
receptors without lowering testosterone levels.
Current recommendations, in addition to calcium and vitamin D supplementation, include DXA

evaluation. Bisphosphonates are indicated for men beginning ADTs if their T score is less than
− 2.5, or between − 1.0 and − 2.0 if other risk factors exist. Depending on patient factors,
alternative treatments include SERMs, denosumab, and antiandrogens. In some cases, women
can be treated with additions of estrogen to the GnRH to maintain BMD. Bisphosphonates are
also effective at maintaining BMD in premenopausal women undergoing 6-month cycles of
GnRH therapy.
4.1.7. Selective Serotonin Receptor Inhibitors (SSRIs)
4.1.7.1. Results using of Selective Serotonin Receptor Inhibitors (SSRIs)
SSRIs including fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram, as well as

serotonin and norepinephrine reuptake inhibitors (SNRIs) such as duloxetine are now widely
prescribed for depression, anxiety disorders, premenstrual syndrome, peripheral neuropathy,
fibromyalgia, and chronic musculoskeletal pain. Several studies have shown that SSRIs are
associated with bone loss and increased fracture risk. Two recent meta-analyses confirmed this
association. Eom and colleagues calculated the adjusted OR for fracture among SSRI users to be
1.69 (95% CI 1.51–1.90; r2 = 89.9%), while Wu and colleagues found a similar OR of 1.73
(95% CI 1.51–1.9; p < 0.001). Fracture risk was highest at the hip and nonvertebral sites
compared with the spine. Dose and duration of SSRIs also contribute to fracture risk, with both
an early increased risk (<6 weeks) and a late risk associated with prolonged use for more than 3–
5 years. A recently published large 10-year longitudinal cohort study examined fracture risk in
SSRI and SNRI users over the age of 50. They found SSRI and NSRI use increased fragility
fractures with a hazard ratio (HR) of 1.88 (95% CI 1.48–2.39). This risk remained elevated even
after multiple confounders were adjusted, with a HR of 1.69 (95% CI 1.32–2.14). Several studies
reported increased fracture risk is highest for postmenopausal women and older men.
Page | 62
Mechanistically, the effect of SSRIs on bone formation and resorption are complex and
incompletely understood. Serotonin receptors found on osteoblasts and osteoclasts regulate bone
homeostasis via endocrine, autocrine, paracrine, and neuronal serotonin pathways. Surprisingly,
SSRI exposure related fractures occur in the absence of declines in BMD, indicating that SSRIs
likely have alternative effects on bone homeostasis.
4.1.7.2. Discussion about Selective Serotonin Receptor Inhibitors (SSRIs)
There are no published guidelines on prevention or treatment of SSRI-induced bone loss.

Clinicians should ensure appropriate calcium and vitamin D supplementation. Patients
considering treatment with SSRIs who have other risk factors for osteoporosis or fracture might
benefit from DXA or FRAX analysis. Treatment decisions should be individualized based on
osteopenia or osteoporotic T scores or fractures risks greater than 3% for hip and greater than
20% for major fractures. At this time, there is no literature to support the use of bisphosphonates
to prevent SSRI fracture risk.
4.1.8. Thiazolidinediones (TZDs)
4.1.8.1. Results using of Thiazolidinediones (TZDs)
TZD are insulin sensitizers used for the treatment of type 2 diabetes mellitus. Two TZDs,
rosiglitazone and pioglitazone, are currently available in the United States and are agonists of
peroxisome proliferator-activated receptor (PPAR ). PPAR is expressed in stromal cells of
the bone marrow, osteoblasts, and osteoclasts, and plays an important role in the differentiation
of precursor cells into osteoblasts. TZDs impair the differentiation of osteoblast precursors,
thereby preventing bone formation leading to osteoporosis. TZDs may act on bone remodeling
by increasing adiposity of bone marrow, decreasing aromatase activity, and promoting osteoclast
differentiation, leading to increased bone resorption. Thus, TZDs reduce bone formation and
increase bone resorption, increasing osteoporosis and fracture risk.
There is sufficient evidence from the published data both in animal models and in humans that
TZDs decrease BMD at the lumbar spine and the hip, and increase fracture risk. A meta-analysis
of 10 randomized trials and two large observational studies indicate TZDs double fractures in
women with type 2 diabetes but not in men. A meta-analysis of three population-based European
Page | 63
cohort studies also found a 1.2–1.5-fold increase in fractures in women but not men taking
TZDs. This study further reveals that prolonged use of TZDs (>25 prescriptions) increases the
risk of extremity fractures more so than vertebral fractures. However, a UK-based observational
study utilizing a large population from general practice research data found that TZDs
significantly increased the risk of nonvertebral fractures independent of age and sex. Fracture
risk is increased even in young women without other risk factors for osteoporosis.
4.1.8.2. Discussion about Thiazolidinediones (TZDs)
No proven strategies exist for reducing the risk of fracture induced by TZDs. Before starting
TZDs, patients should be evaluated for fracture risk by FRAX analysis or DXA. According to
the International Diabetes Foundation, metformin and sulfonylureas should be used as first- and
second-line drugs for type 2 diabetes followed by TZDs and other agents. TZDs should be
avoided in patients with established osteoporosis and should be stopped in those with a high risk
of fracture.
4.1.9. Calcineurin Inhibitors
4.1.9.1. Results using of Calcineurin Inhibitors
Calcineurin inhibitors, including cyclosporine (CsA) and tacrolimus (FK506), have been widely
used as immune suppression to prevent organ transplant rejection and for autoimmune disorders.
Both are associated with bone loss and increased fracture, although the exact mechanisms are not
known. In vitro, calcineurin inhibitors inhibit osteoclastogenesis and osteoclast activity via
reductions in Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1). However, in animal
models and humans, these drugs cause dose- and duration-dependent bone loss with excessive
osteoclastogenesis. Additionally, there are indirect effects on osteocalcin and vitamin D
metabolism, leading to secondary hyperparathyroidism and subsequent high bone turnover
osteopenia.
The adverse bone effect of calcineurin inhibitors in humans is difficult to delineate due to the
confounding effects of poor bone health prior to organ transplantation and the use of GCs post
transplantation. Several studies suggest that calcineurin inhibitors cause bone loss and fragility
fractures in transplant patients and the effect is dose and duration dependent. However, when
Page | 64
CsA or FK506 are given as monotherapy or in low-GC (10 mg daily) treatment plans, BMD is
preserved and even increased. CsA use in rheumatic diseases at doses below 5 mg/kg/day has not
been reported to have clinically significant bone loss. A multicenter, cross-sectional study of
women with rheumatoid arthritis on CsA found that only women treated for over 24 months had
a decrease in BMD, but this decrease was not associated with an increased risk of fracture.
4.1.9.2. Discussion about Calcineurin Inhibitors
The prevention or treatment of post-transplant osteoporosis are limited in terms of large,

placebo-controlled studies. Many small studies in kidney, liver, and heart transplant show BMD
preservation with bisphosphonates. Guidelines from the National Kidney Foundation support
BMD evaluation with DXA prior to transplantation and 1 and 2 years post transplantation. If the
T score is − 2.0, in addition to calcium and vitamin D supplementation, bisphosphonates are
indicated. Given the disparate studies showing preservation of BMD and significant BMD loss in
various populations, further studies are needed to provide guidance for monitoring and treating
bone health in the presence of calcineurin inhibitors.
4.1.10. Anticoagulants
4.1.10.1. Results using of Anticoagulants
Heparin has been in clinical use for over 50 years for the prevention and treatment of venous
thromboembolism. Although short-term use is not associated with reductions in BMD or
increased fractures, long-term use leads to reductions in BMD and increased fractures.
Mechanistically, unfractionated heparin inhibits osteoblast differentiation and function, leading
to decreases in bone formation. Additionally, heparin increases bone resorption by leading to
reductions in OPG, favoring RANKL-induced osteoclast differentiation.
Several studies have shown that up to 30% of heparin-treated pregnant women will have
decreases in BMD with 2.2–3.6% developing fractures despite their young age. The incidence of
vertebral fractures in nonpregnant women on long-term heparin is 15% and often occurs within 6
months of starting heparin therapy. Heparin-induced bone loss is dose dependent and highly
reversible upon discontinuation. Small studies suggest that low molecular weight heparin
(LMWH) is associated with fewer fragility fractures compared with unfractionated heparin.
Page | 65
However, a large prospective study in pregnant patients found no differences between
unfractionated heparin and LMWH. Newer heparins, including fondaparinux, have no effect on
osteoblast differentiation or function in vitro and are predicted to be bone neutral. Clinical
studies supporting this hypothesis are lacking at this time.
Controversy surrounds the effects of the oral anticoagulant, warfarin, on bone density and
fracture. Mechanistically, warfarin decreases the carboxylation and calcium-binding properties
of osteocalcin and is predicted to negatively impact BMD. Many small cross-sectional and
retrospective studies indicate that warfarin is associated with reductions in BMD and increases in
vertebral and rib fractures.
4.1.10.2. Discussion about Anticoagulants
However,the studies have found no significant effects on BMD or fractures in warfarin users
compared with controls. At this time, data are inconclusive as to the impact of warfarin on bone.
There are no published guidelines for the prevention or treatment of heparin or oral
anticoagulant-induced bone loss. Because most patients on long-term heparins are pregnant,
bisphosphonates have not been studied in these patients due to concerns for the fetal skeleton. In
addition to calcium and vitamin D supplementation in patients at high risk for osteoporosis,
LMWH or fondaparinux may be preferred over unfractionated heparin for thromboprophylaxis.
4.1.11. Chemotherapy Agents
4.1.11.1. Results & Discussion of Chemotherapy Agents
Some chemotherapeutic agents are associated with excessive bone loss. High-dose methotrexate
can directly cause bone loss; whereas ifosfamide leads to bone loss secondary to renal tubular
phosphate wasting. Other drugs, like cyclophosphamide, indirectly induce bone loss due to
negative effects on gonadal tissues.
Page | 66
Chapter-Five
Conclusion
Page | 67
5.1. Conclusion
Osteoporosis is characterized by low bone mineral density (BMD) and loss of the structural and
biomechanical properties that are required to maintain bone homeostasis. Physicians are
knowledgeable about the association of osteoporosis with aging, postmenopausal status, and
secondary causes, including chronic illnesses or lifestyle issues that promote osteoporosis.
However, many widely used medications have now been shown to cause decreases in BMD and
increase fractures, and physicians may not be aware of these effects. Epidemiologic studies
provide valuable information about medications that place patients at risk for drug-induced
osteoporosis. While glucocorticoids (GCs) are most commonly associated with drug-induced
osteoporosis, the use of several other therapeutic agents increase the risk of significant bone loss
and fracture. These medications include proton pump inhibitors (PPIs), selective serotonin
receptor inhibitors (SSRIs), thiazolidinediones (TZDs), anticonvulsants, medroxyprogesterone
acetate (MPA), hormone deprivation therapy, calcineurin inhibitors, chemotherapies, and
anticoagulants. Drug-induced osteoporosis is a significant health problem and many physicians
are unaware that many commonly prescribed medications contribute to significant bone loss and
fractures. In addition to glucocorticoids, proton pump inhibitors, selective serotonin receptor
inhibitors, thiazolidinediones, anticonvulsants, medroxyprogesterone acetate, aromatase
inhibitors, androgen deprivation therapy, heparin, calcineurin inhibitors, and some
chemotherapies have deleterious effects on bone health. Furthermore, many patients are treated
with combinations of these medications, possibly compounding the harmful effects of these
drugs. Increasing physician awareness of these side effects will allow for monitoring of bone
health and therapeutic interventions to prevent or treat drug-induced osteoporosis.
Page | 68
Chapter-Six
Reference
Page | 69
6.1. Reference
Adachi J., Saag K., Delmas P., Liberman U., Emkey R., Seeman E., et al. . (2001) Two-year
effects of alendronate on bone mineral density and vertebral fracture in patients receiving
glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis
Rheum 44: 202–211 [PubMed] [Google Scholar]
American College of Obstetricians & Gynecologists Committee on Gynecologic Practice

(2008) ACOG Committee Opinion No. 415: Depot medroxyprogesterone acetate and bone
effects. Obstet Gynecol 112: 727–730 [PubMed] [Google Scholar]
An Y, Zhang H, Wang C, Jiao F, Xu H, Wang X, Luan W, Ma F, Ni L, Tang X, Liu M, Guo

W, Yu L. FASEB J. doi: 10.1096/fj.201802805RR. [Epub ahead of print]
Backos M., Rai R., Thomas E., Murphy M., Dore C., Regan L. (1999) Bone density changes in
pregnant women treated with heparin: a prospective, longitudinal study. Hum Reprod 14: 2876–
2880 [PubMed] [Google Scholar]
Barker KL, Newman M, Stallard N, Leal J, Minns Lowe C, Javaid MK, Noufaily A, Adhikari
A, Hughes T, Smith DJ, Gandhi V, Cooper C, Lamb SE.
Health Technol Assess. doi: 10.3310/hta23440.
Bartl R. (2007) [Antiepileptic drug-induced osteopathy. Subtypes, pathogenesis, prevention,

early diagnosis and treatment]. Dtsch Med Wochenschr 132: 1475–1479 [PubMed] [Google
Scholar]
Bazelier M., De Vries F., Vestergaard P., Herings R., Gallagher A., Leufkens H., et al. .
(2013) Risk of fracture with thiazolidinediones: an individual patient data meta-analysis. Front
Endocrinol (Lausanne) 4: 11. [PMC free article] [PubMed] [Google Scholar]
Bonadonna S., Burattin A., Nuzzo M., Bugari G., Rosei E., Valle D., et al. . (2005) Chronic
glucocorticoid treatment alters spontaneous pulsatile parathyroid hormone secretory dynamics in
human subjects. Eur J Endocrinol 152: 199–205 [PubMed] [Google Scholar]
Brufsky A., Bosserman L., Caradonna R., Haley B., Jones C., Moore H., et al. .
(2009) Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in
postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-
month follow-up results. Clin Breast Cancer 9: 77–85 [PubMed] [Google Scholar]
Canalis E., Mazziotti G., Giustina A., Bilezikian J. (2007) Glucocorticoid-induced osteoporosis:
pathophysiology and therapy. Osteoporos Int 18: 1319–1328 [PubMed] [Google Scholar]
Caraballo P., Heit J., Atkinson E., Silverstein M., O’Fallon W., Castro M., et al. . (1999) Long-
term use of oral anticoagulants and the risk of fracture. Arch Intern Med 159: 1750–1756
[PubMed] [Google Scholar]
Page | 70
Che J, Yang J, Zhao B, Zhang G, Wang L, Peng S, Shang P. Biol Trace Elem Res. doi:
10.1007/s12011-019-01867-4. [Epub ahead of print]
Clark M., Sowers M., Nichols S., Levy B. (2004) Bone mineral density changes over two years
in first-time users of depot medroxyprogesterone acetate. Fertil Steril 82: 1580–1586
Dardonville Q, Salguiero E, Rousseau V, Chebane L, Faillie JL, Gautier S, Montastruc

JL, Carvajal A, Bagheri H. Eur J Clin Pharmacol. doi: 10.1007/s00228-019-02743-9. [Epub
ahead of print]
Dore R., Cohen S., Lane N., Palmer W., Shergy W., Zhou L., et al. . (2010) Effects of
denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis
receiving concurrent glucocorticoids or bisphosphonates. Ann Rheum Dis 69: 872–875
Douglas I., Evans S., Pocock S., Smeeth L. (2009) The risk of fractures associated with
thiazolidinediones: a self-controlled case-series study. PLoS Med 6: e1000154. [PMC free
article] [PubMed]
Drezner M. (2004) Treatment of anticonvulsant drug-induced bone disease. Epilepsy

Behav 5(Suppl. 2): S41–S47 [PubMed] [Google Scholar]
Eggemoen, A. R., Knutsen, K. V et al. (2013) Vitamin D status in recently arrived

immigrants from Africa and Asia: a cross-sectional study from Norway of children,
adolescents and adults. BMJ Open. [Online] Available from:
http://bmjopen.bmj.com/content/3/10/e003293.full [Accessed: 4th November 2016]
Ensrud K., Walczak T., Blackwell T., Ensrud E., Barrett-Connor E., Orwoll E.; Osteoporotic
Fractures in Men Study Research Group (2008) Antiepileptic drug use and rates of hip bone loss
in older men: a prospective study. Neurology 71: 723–730 [PMC free article] [PubMed] [Google
Scholar]
Eom C., Lee H., Ye S., Park S., Cho K. (2012) Use of selective serotonin reuptake inhibitors and
risk of fracture: a systematic review and meta-analysis. J Bone Miner Res 27: 1186–1195
Fiore C., Tamburino C., Foti R., Grimaldi D. (1990) Reduced axial bone mineral content in
patients taking an oral anticoagulant. South Med J 83: 538–542 [PubMed] [Google Scholar]
Gehlen M, Lazarescu AD, Hinz C, Schwarz-Eywill M, Pfeifer M, Balasingam S, Maier A.

Clin Rheumatol. doi: 10.1007/s10067-019-04758-0. [Epub ahead of print]
Goffin E., Devogelaer J., Lalaoui A., Depresseux G., De Naeyer P., Squifflet J., et al. .
(2002) Tacrolimus and low-dose steroid immunosuppression preserves bone mass after renal
transplantation. Transpl Int 15: 73–80 [PubMed] [Google Scholar]
Page | 71
Golob AL, Laya MB (May 2015). "Osteoporosis: screening, prevention, and management". The
Medical Clinics of North America. 99 (3): 587– 606.
doi:10.1016/j.mcna.2015.01.010. PMID 25841602
Gronholz, M.J., (2008) Prevention, diagnosis, and management of osteoporosis-related

fracture: a multifactoral osteopathic approach. The Journal of the American Osteopathic
Association, 108(10), pp.575-585.
Gray S., Lacroix A., Larson J., Robbins J., Cauley J., Manson J., et al. . (2010) Proton pump
inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results
from the Women’s Health Initiative. Arch Intern Med 170: 765–771 [PMC free
article] [PubMed] [Google Scholar]
Grey A. (2009) Thiazolidinedione-induced skeletal fragility – mechanisms and

implications. Diabetes Obes Metab 11: 275–284 [PubMed] [Google Scholar]
Grossman J., Gordon R., Ranganath V., Deal C., Caplan L., Chen W., et al. . (2010) American
College of Rheumatology 2010 recommendations for the prevention and treatment of
glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 62: 1515–1526
Hadji P., Aapro M., Body J., Bundred N., Brufsky A., Coleman R., et al. . (2011) Management
of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer:
practical guidance for prevention and treatment. Ann Oncol 22: 2546–2555 [PubMed] [Google
Scholar]
Hamson, C., Goh, L., Samanta, A. (2002) Comparative study of bone mineral density,
calcium and vitamin D status in the Gujrati and white populations of Leicester. BMJ Post
graduate Medical Journal. [Online] Available from:
http://pmj.bmj.com/content/79/931/279.full [Accessed: 4th November 2016]
Handschin A., Trentz O., Hoerstrup S., Kock H., Wanner G., Trentz O. (2005) Effect of low
molecular weight heparin (dalteparin) and fondaparinux (Arixtra) on human osteoblasts in
vitro. Br J Surg 92: 177–183 [PubMed] [Google Scholar]
Jin YZ, Lee JH, Xu B, Cho M. BMC Musculoskelet Disord. doi: 10.1186/s12891-019-2769-8.
Lau Y., Ahmed N. (2012) Fracture risk and bone mineral density reduction associated with
proton pump inhibitors. Pharmacotherapy, 32, 67–79 [PubMed] [Google Scholar]
Liu B., Anderson G., Mittmann N., To T., Axcell T., Shear N. (1998) Use of selective serotonin-
reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly
people. Lancet 351: 1303–1307 [PubMed] [Google Scholar]
Page | 72
Loke Y., Singh S., Furberg C. (2009) Long-term use of thiazolidinediones and fractures in type 2
diabetes: a meta-analysis. CMAJ 180: 32–39 [PMC free article] [PubMed] [Google Scholar]
Lopez L., Chen M., Mullins S., Curtis K., Helmerhorst F. (2012) Steroidal contraceptives and
bone fractures in women: evidence from observational studies. Cochrane Database Syst Rev 8:
CD009849. [PubMed] [Google Scholar]
Mitwally M., Gotlieb L., Casper R. (2002) Prevention of bone loss and hypoestrogenic
symptoms by estrogen and interrupted progestogen add-back in long-term GnRH-agonist down-
regulated patients with endometriosis and premenstrual syndrome. Menopause 9: 236–241
Mirza F, Canalis E (September 2015). "Management of endocrine disease: Secondary

osteoporosis: pathophysiology and management". Eur J Endocrinol (Review). 173 (3): R131–
51. doi:10.1530/EJE-15-0118. PMC 4534332. PMID 25971649.
Ngamruengphong S., Leontiadis G., Radhi S., Dentino A., Nugent K. (2011) Proton pump
inhibitors and risk of fracture: a systematic review and meta-analysis of observational
studies. Am J Gastroenterol 106: 1209–1218; quiz 1219. [PubMed] [Google Scholar]
Pacher P., Ungvari Z. (2001) Selective serotonin-reuptake inhibitor antidepressants increase the
risk of falls and hip fractures in elderly people by inhibiting cardiovascular ion channels. Med
Hypotheses 57: 469–471 [PubMed] [Google Scholar]
Reid D., Devogelaer J., Saag K., Roux C., Lau C., Reginster J., et al. .; HORIZONE
Investigators (2009) Zoledronic acid and risedronate in the prevention and treatment of
glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy,
randomised controlled trial. Lancet 373: 1253–1263 [PubMed] [Google Scholar]
Richards J., Papaioannou A., Adachi J., Joseph L., Whitson H., Prior J., et al. .; Canadian
Multicentre Osteoporosis Study Research Group (2007) Effect of selective serotonin reuptake
inhibitors on the risk of fracture. Arch Intern Med 167: 188–194 [PubMed] [Google Scholar]
Saag K., Shane E., Boonen S., Marin F., Donley D., Taylor K., et al. . (2007) Teriparatide or
alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 357: 2028–2039
Simonelli, C; et al. (July 2006). "ICSI Health Care Guideline: Diagnosis and Treatment of
Osteoporosis, 5th edition". Institute for Clinical Systems Improvement. Archived from the
original (PDF) on 18 July 2007. Retrieved 8 April 2008.
Steinbuch M., Youket T., Cohen S. (2004) Oral glucocorticoid use is associated with an
increased risk of fracture. Osteoporos Int 15: 323–328 [PubMed] [Google Scholar]
Page | 73
Tannirandorn P., Epstein S. (2000) Drug-induced bone loss. Osteoporos Int 11: 637–659
Targownik L., Lix L., Metge C., Prior H., Leung S., Leslie W. (2008) Use of proton pump
inhibitors and risk of osteoporosis-related fractures. CMAJ 179: 319–326 [PMC free
Tatsuno I., Sugiyama T., Suzuki S., Yoshida T., Tanaka T., Sueishi M., et al. . (2009) Age
dependence of early symptomatic vertebral fracture with high-dose glucocorticoid treatment for
collagen vascular diseases. J Clin Endocrinol Metab 94: 1671–1677 [PubMed] [Google Scholar]
Tsai JN, Lee H, David NL, Eastell R, Leder BZ. Lancet Diabetes Endocrinol. pii: S2213-
8587(19)30255-4. doi: 10.1016/S2213-8587(19)30255-4. [Epub ahead of print]
Vestergaard P., Rejnmark L., Mosekilde L. (2006b) Proton pump inhibitors, histamine H2
receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int 79:
76–83 [PubMed] [Google Scholar]
Vestergaard P., Rejnmark L., Mosekilde L. (2008a) The effects of depot medroxyprogesterone
acetate and intrauterine device use on fracture risk in Danish women. Contraception 78: 459–464
Weinstein R. (2012) Glucocorticoid-induced osteoporosis and osteonecrosis. Endocrinol Metab

Clin North Am 41: 595–611 [PMC free article] [PubMed] [Google Scholar]
Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, Coyle D, Tugwell P

(January 2008). "Alendronate for the primary and secondary prevention of osteoporotic fractures
in postmenopausal women". The Cochrane Database of Systematic Reviews (1):
CD001155. doi:10.1002/14651858.CD001155.pub2. PMID 18253985.
Wu Q., Bencaz A., Hentz J., Crowell M. (2012) Selective serotonin reuptake inhibitor treatment
and risk of fractures: a meta-analysis of cohort and case-control studies. Osteoporos Int 23: 365–
375 [PubMed] [Google Scholar]
Yang Y., Lewis J., Epstein S., Metz D. (2006) Long-term proton pump inhibitor therapy and risk
of hip fracture. JAMA 296: 2947–2953 [PubMed] [Google Scholar]
Yao R, Nishii K, Kito T, Teranishi T, Sugiyama T, Sakai K, Matsubara M, Yamada K.

Okajimas Folia Anat Jpn. doi: 10.2535/ofaj.96.13.
Yu E., Bauer S., Bain P., Bauer D. (2011) Proton pump inhibitors and risk of fractures: a meta-
analysis of 11 international studies. Am J Med 124: 519–526 [PMC free
Zawawi M., Dharmapatni A., Cantley M., McHugh K., Haynes D., Crotti T. (2012) Regulation
of ITAM adaptor molecules and their receptors by inhibition of calcineurin-NFAT signalling
Page | 74
during late stage osteoclast differentiation. Biochem Biophys Res Commun 427: 404–409
Zhang W, Xue K, Gao Y, Huai Y, Wang W, Miao Z, Dang K, Jiang S, Qian A.

Life Sci. doi: 10.1016/j.lfs.2019.116820. [Epub ahead of print]
Zhao J, Liu S, Zhang W, Ni L, Hu Z, Sheng Z, Yin B. Biosci Rep. doi: 10.1042/BSR20191405.

[Epub ahead of print]
https://www.emedicinehealth.com/osteoporosis/article_em.htm#what_is_osteoporosis
https://www.emedicinehealth.com/slideshow_osteoporosis_pictures/article_em.htm
https://www.iofbonehealth.org/what-is-osteoporosis
https://www.medicalnewstoday.com/articles/155646.php
https://www.medicinenet.com/osteoporosis/article.htm#osteoporosis_facts
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206646/
https://www.ncbi.nlm.nih.gov/pubmed/31476308
https://www.healthline.com/health/osteoporosis
https://www.versusarthritis.org/about-arthritis/conditions/osteoporosis/
https://en.wikipedia.org/wiki/Osteoporosis
Page | 75

Final Project PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Final Project PDF

Uploaded by

Copyright:

Available Formats

Chapter-One

Osteoporosis may be due to lower-than-normal maximum bone mass and greater-than-normal

1.3. Signs & Symptoms of Osteoporosis

Figure No : 02. Human skeleton

Figure No : 03. Fractures of bone

Figure No : 04. Fractures of spine

Figure No : 05. Stress fracture

1.3.4. Hip Fracture

Figure No : 06. Hip fracture

Figure No : 07. Bone density deterioration

Factors that determine bone strength include:

1.5. Risk Factors of Osteoporosis

Figure No : 08. Bone density peaks (male & female)

1.5.3. Medical disorders

People with rheumatologic disorders such as rheumatoid arthritis, ankylosing spondylitis,

Figure No : 09. Calcium homeostasis

Steroid-induced osteoporosis (SIOP) arises due to use of glucocorticoids – analogous to

Barbiturates, phenytoin and some other enzyme-inducing antiepileptics – these probably

L-Thyroxine over-replacement may contribute to osteoporosis, in a similar fashion as

Anticoagulants- long-term use of heparin is associated with a decrease in bone density,

Chronic lithium therapy has been associated with osteoporosis.

The underlying mechanism in all cases of osteoporosis is an imbalance between bone

Figure No : 10. Pathogenesis of osteoporotic fractures

The activation of osteoclasts is regulated by various molecular signals, of

Figure No : 11. Osteoporosis locations

Figure No : 12. Osteoclast

Light micrograph of osteoblasts, several displaying a prominent Golgi apparatus, actively

Figure No : 13. Osteoblast

In addition to the detection of abnormal BMD, the diagnosis of osteoporosis requires

1.7.1. Conventional radiography

1.7.2. Dual-energy X-ray

Table No : 01. Diagnostic guidelines of osteoporotic

Category T-score range % young women

Normal T-score ≥ − 1.0 85%

Osteopenia − 2.5 < T-score < − 1.0 14%

Osteoporosis T-score ≤ − 2.5 0.6%

Severe osteoporosis T-score ≤ −2.5 with fragility fracture

Figure No : 15. DEXA scan of bone density

Osteomalacia and rickets decreased decreased elevated elevated soft bones

Osteomalacia and rickets decreased decreased elevated elevated soft bones

 Ensure a nutritious diet with adequate calcium intake

 Green vegetables like broccoli, curly kale

1.9.3. Other nutrition

Method and Material

Zhang W, Xue K, Gao Y, Huai Y, Wang W, Miao Z, Dang K, Jiang S, Qian A.

MATERIALS AND METHODS:

Che J, Yang J, Zhao B, Zhang G, Wang L, Peng S, Shang P.

Biol Trace Elem Res. doi: 10.1007/s12011-019-01867-4. [Epub ahead of print]

Available link : https://www.ncbi.nlm.nih.gov/pubmed/31473898

3.3. MiR-128 inhibits the osteogenic differentiation in osteoporosis by down-

Zhao J, Liu S, Zhang W, Ni L, Hu Z, Sheng Z, Yin B.

Biosci Rep. doi: 10.1042/BSR20191405. [Epub ahead of print]

Available link : https://www.ncbi.nlm.nih.gov/pubmed/31477582

3.4. Combination denosumab and high dose teriparatide for postmenopausal

Tsai JN, Lee H, David NL, Eastell R, Leder BZ.

Lancet Diabetes Endocrinol. pii: S2213-8587(19)30255-4. doi: 10.1016/S2213-8587(19)30255-

Available link : https://www.ncbi.nlm.nih.gov/pubmed/31447409

3.5. Drug-induced osteoporosis/osteomalacia: analysis in the French and

Dardonville Q, Salguiero E, Rousseau V, Chebane L, Faillie JL, Gautier S, Montastruc

Available link : https://www.ncbi.nlm.nih.gov/pubmed/31468068

3.6. Effect of medications on prevention of secondary osteoporotic vertebral

Jin YZ, Lee JH, Xu B, Cho M.

BMC Musculoskelet Disord. doi: 10.1186/s12891-019-2769-8.