Secondary Osteoporosis :

Pathogenesis & Diagnosis

Laksmi Sasiarini
2018
Introduction
Osteoporosis is a skeletal disorder characterized by low bone
mass and microarchitectural deterioration of the skeleton
leading to bone fragility and a predisposition to fractures.

• Idiopathic osteoporosis
• Secondary osteoporosis (medical conditions and medications)

It is important to exclude secondary causes of osteoporosis as

the treatment of these patients may differ, and its response may
be limited if the underlying disorder is unrecognized and left
untreated.
 Secondary causes of osteoporosis
Endocrine disorders
Hyperthyroidism, hyperparathyroidism, cushing's syndrome (exogenous or endogenous),
hypogonadism, acromegaly, diabetes mellitus, idiopathic hypercalciuria, early menopause.
Gastrointestinal diseases
Inflammatory bowel disease, severe liver diseases, malabsorption syndromes
Hematologic diseases
Multiple myeloma, mastocytosis
Rheumatological and autoimmune diseases
Rheumatoid arthritis, SLE, ankylosing spondylitis, multiple sclerosis
Genetic disorders
Osteogenesis imperfecta, hypophosphatasia
Drug induced osteoporosis
Steroids, anti-epileptic drugs, anti-depressants, glitazones, proton pump inhibitors (PPIs),
thyroxine, aromatase inhibitors, GnRH agonists
Others: Immobilization, smoking, low BMI, HIV infection, heavy alcohol use, organ
transplantation, poor accrual of bone health from deprivation in, early years from either
systemic illnesses
Investigations for secondary osteoporosis.
More routinely done:
• Full blood count
• The hemoglobin levels are of especial interest as both a marker of chronic
disease and also the triad of anemia, hypercalcemia and increased
creatinine may signify multiple myeloma
• Urea, electrolytes and creatinine - in order not to miss renal bone disease
• Thyroid function screen
• 25-OH Vitamin D
• Calcium with or without parathyroid hormone
• Testosterone for males
• 24 hours urine calcium
• Liver function test
Investigations for secondary osteoporosis.

Other tests to consider:

• Screening for endogenous Cushing's syndrome when suspected such as
the overnight dexamethasone suppression test or the 24 hours urine free
cortisol
• Screening for coeliac's disease - this is a rare condition in East and South
East Asia and as such rarely is a first line test to be carried out.
• Protein electrophoresis for multiple myeloma given that this is relatively
rare and also relatively more expensive to carry out requiring specialised
laboratories, it is generally not first line of choice for investigations.
 Diabetes and Bone Metabolism

Insulin is an anabolic hormone, which acts on bone

through insulin receptors expressed by osteoblasts—IRS-1
and IRS-2 (insulin-like substrate).
• Stimulation of IRS-1 affects bone turnover
• Stimulation of IRS-2 shifts the balance between bone
formation and resorption.

Insulin stimulates osteoblast proliferation, promotes

collagen synthesis.
 TYPE 1 and 2 DIABETES MELLITUS
Studies in bone histomorphometry in type 1 diabetes 
low turnover of bone with reduction in bone formation (↓
osteocalcin) and, to a lesser degree, bone resorption.
The anabolic effects of insulin may be mediated through the
insulin like growth factor 1 ( IGF 1) pathway
low levels of insulin and IGF 1 may impair
osteoblast function.

TYPE 2 DIABETES
MELLITUS
HYPERGLYCEMIA
• Increased production of IL-6
in osteoblast line cells
(IL-6 stimulates osteoclasts to
resorb bone)
• The accumulation of AGEs HYPOGLYCEMIA
in collagen leads to inferior • Increased risk of falls
bone quality and strength • Hypoglycemic treatments
(glycated collagen inhibits
could modulate the risk of
expression in osteoblasts)
fractures (TZD)
• Hypercalciuria, leading to
decreased levels of calcium

Jackuliak P, Payer J. International Journal of Endocrinology 2014

 Am J Epidemiol 2007;166:495–505

The 16 eligible studies (two case-control studies and 14 cohort studies)

included 836,941 participants and 139,531 incident cases of fracture.
• Type 2 diabetes was associated with an increased risk of hip fracture in
both men (summary relative risk (RR)=2.8, 95% confidence interval (CI):
1.2, 6.6) and women (summary RR=2.1, 95% CI: 1.6, 2.7).
• All six of these studies found a statistically significant positive association
between type 1 diabetes and hip fracture incidence (range of individual
RRs, 1.7–12.3)
• The association between type of diabetes and hip fracture incidence was
stronger for type 1 diabetes (summary RR=6.3, 95% CI: 2.6, 15.1) than for
type 2 diabetes (summary RR=1.7, 95% CI: 1.3, 2.2).
 Hyperthyroidism on Bone Density
• In hyperthyroidism, bone turnover is accelerated 2x, with a
net loss of bone.
• Receptors for thyroid hormones and TSH are present in bone
 may act directly on both hosteoclasts and osteoblasts.
• The severity of hyperthyroidism correlates with the
• decrease in BMD and the increase in fracture risk.
• Hyperthyroidism affects cortical bone to a greater extent than
trabecular bone and is best measured by BMD at the distal
forearm.
• Women over 65 years old with a TSH <0.1 have the greatest
fracture risk.
• Normalizing thyroid function alone is able to effect some
reversal of bone loss.

• Subclinical hyperthyroidism contributes to an estimated

additional 1% bone loss per year in these individuals
 Glucocorticoid-induced osteoporosis
(GIO)

• The most common cause of secondary osteoporosis.

• The first cause before 50 years.
• The first iatrogenic cause of the disease.
• Fractures have been reported in as many as 30 to 50 percent
of glucocorticoid users .
• The incidence of fracture is higher with advanced age, low
bone strength at the beginning of GC treatment, larger dose,
and longer duration of glucocorticoid therapy.
• The increase in fracture risk is immediate, as early as 3
months after the initiation of therapy and reverses sharply
after discontinuation of GCs.

• The increased risk of fracture has been reported with doses of

prednisone or its equivalent as low as 2.5 to 7.5 mg daily.
 EXCESS OF GLUCOCORTICOID

BONE CYTOKINES AND CALCIUM METABOLISM MUSCLE

ENDOCRINE SYSTEMS ↓Intestinal absorption Proteolysis of
↑Renal excretion myofibrils

OSTEOCYTES OSTEOBLASTS OSTEOCLASTS ↓TGF-

↑Function ↓Differentiation ↑Differentiation ↓GH/IGF-1
↓Apoptosis ↓Function ↓Apoptosis ↓IGF-BPs
↑Apoptosis

↓Sex steroid ↓Fibrils

↓Bone Formation ↑Bone Resorption Negative calcium balance Myopathy

↓Bone Quality ↓Bone Mass

Increased Risk Fracture ↑Risk of falls Muscle weakness

Diagnosis
Bone Mineral Density
• Glucocorticoids result in rapid bone loss and an increase in
fracture risk that cannot be fully explained by changes in
BMD.
• At similar levels of BMD, postmenopausal women taking GCs
have considerably higher risk of fracture than controls not
using GCs.
Diagnosis
WHO fracture risk assessment (FRAX) tool
Limitations of FRAX :
• does not take into account the dose of GCs and the duration
of use.
• does not take into account the difference in risk between
prior and current use of GC
• the predictive value of FRAX has been mainly validated for
nonvertebral fractures although the principal risk in GCs users
is for vertebral fractures.
 Fracture risk categories in GC-treated patients
Adults ≥40 years of age Adults <40 years of age
High fracture risk • Prior osteoporotic fracture(s)
• Hip or spine BMD
T score ≤-2.5 in men age ≥50 years
and postmenopausal women
Prior osteoporotic fracture(s)
• FRAX* (GC-adjusted†) 10-year risk of
major osteoporotic fracture‡ ≥20%
• FRAX* (GC-adjusted†) 10-year risk of hip
fracture ≥3%
Moderate fracture • FRAX* (GC-adjusted†) 10-year risk of Hip or spine bone mineral
risk major osteoporotic fracture‡ 10–19% density Z score <-3 or
• FRAX* (GC-adjusted†) 10-year risk of hip rapid bone loss (≥10% at the hip or
fracture >1% and <3% spine over 1 year) and
Continuing GC treatment at ≥7.5
mg/day for ≥6 months
Low fracture risk • FRAX* (GC-adjusted†) 10-year risk of
major osteoporotic fracture‡ <10% None of above risk factors other
• FRAX* (GC-adjusted†) 10-year risk of hip than GC treatment
fracture ≤1%
(American College of Rheumatology Guideline 2017)
* https//www.shef.ac.uk/FRAX/tool.jsp.
† Increase the risk generated with FRAX by 1.15 for major osteoporotic fracture and 1.2 for hip fracture
if glucocorticoid (GC) treatment is .7.5 mg/day (e.g., if hip fracture risk is 2.0%, increase to 2.4%).
‡ Major osteoporotic fracture includes fractures of the spine (clinical), hip, wrist, or humerus
 Reassessment of
fracture risk
(American College of Rheumatology
Guideline 2017)

Very high-dose GC treatment was defined as treatment with prednisone ≥30 mg/day
and a cumulative dose of.5 gm in the past year.
Clinical fracture risk reassessment
• History with the details of glucocorticoid (GC) use (dose, duration,
pattern of use)

• Evaluation for falls, fractures, frailty

• Other osteoporosis (OP) risk factors (malnutrition, significant

weight loss or low body weight, hypogonadism, secondary
hyperparathyroidism, thyroid disease, family history of hip fracture,
history of alcohol use or smoking)

• Clinical comorbidities

• Physical examination including measurement of weight and height

(without shoes), testing of muscle strength, and assessment for
other clinical findings of undiagnosed fracture (i.e., spinal
tenderness, deformity,and reduced space between lower ribs and
upper pelvis) as appropriate given the patient’s age.
Thank You