SECONDARY OSTEOPOROSIS

Introduction
Secondary osteoporosis results from specific clinical disorders that are potentially reversible.
Up to 30% of postmenopausal women and 50% of men with osteoporosis may have an
underlying cause. The underlying pathogenesis of secondary osteoporosis is often
multifactorial. Correctly treating the cause may ameliorate fracture risk and avoid unnecessary
treatment with antiresorptive drugs.
Clinical assessment
Secondary causes of osteoporosis should be considered in patients who suffer a fragility
fracture when ‘traditional’ risk factors are insufficient to explain the injury. People with a bone
mineral density Z-score –2.5 or less may also have secondary osteoporosis. (The Z-score is a
comparison to age-matched, sex-matched individuals.) Clues to an underlying secondary cause
include an atypical fracture, the severity of osteoporosis and the presence of clinical features
found through history and clinical examination (e.g. anaemia, malabsorption, amenorrhoea,
constitutional symptoms or specific endocrinopathies). A careful drug history may identify
possible causes. While corticosteroids are well known to cause osteoporosis and fragility
fractures, a number of other drugs also increase fracture risk. However, not all patients with
secondary osteoporosis will present with the classic signs of the underlying condition. They
may have subclinical disease at the time of their fracture or when the low bone mineral density
is detected, with osteoporosis being the first manifestation of their underlying condition.
Identifying the cause
When a patient has clinical evidence of an underlying cause of osteoporosis, the necessary
investigations may be straightforward. In an otherwise healthy patient with no specific clinical
signs, a range of investigations may be required to identify a secondary cause of osteoporosis.
The prevalence of undiagnosed secondary causes of osteoporosis is unknown and there are no
guidelines regarding appropriate laboratory tests for the otherwise healthy patient. In any
patient suspected of having secondary osteoporosis, most experts recommend evaluation of
bone and mineral metabolism with blood tests for calcium, phosphate, alkaline phosphatase,
25-hydroxyvitamin D, parathyroid hormone, liver and kidney function, full blood count and
thyroid-stimulating hormone.
In those with severe osteoporosis (multiple fractures or bone mineral density T-score <–3.0)
without specific clinical findings, additional tests should be performed. These tests include
serum protein electrophoresis, free light chain assay, markers of inflammation, coeliac serology
and total IgA, sex steroids (testosterone in men and oestradiol in women) and 24-hour urinary
free cortisol.
A 24-hour urinary calcium collection is indicated if there are abnormalities of serum calcium
or parathyroid hormone. The role of bone turnover markers, such as telopeptides, in the
diagnosis of osteoporosis is controversial. Currently, in specialists’ clinics, their clinical role is
in monitoring treatment efficacy. Several small cross-sectional studies have evaluated the yield
of combined laboratory investigations in identifying an underlying cause of osteoporosis in
otherwise asymptomatic patients. In studies of 173 and 204 postmenopausal women, the three
most common findings were hypercalciuria, malabsorption (vitamin D deficiency) and
hyperparathyroidism.
In the study of 204 women, hyperparathyroidism was detected in 35%, although less than 10%
had primary hyperparathyroidism with hypercalcaemia. A cost-benefit analysis of the
investigations was not performed in either of these studies. There are no large studies assessing
the frequency and cost benefit of investigations for secondary osteoporosis.
a. Gonadal hormone insufficiency
Oestrogen lack is an important factor in postmenopausal osteoporosis. It also accounts for
osteoporosis in younger women who have undergone oophorectomy, and in pubertal girls with
ovarian agenesis and primary amenorrhoea (Turner’s syndrome). Treatment is the same as for
postmenopausal osteoporosis.
Amenorrhoeic female athletes, and adolescents with anorexia nervosa, may become
osteoporotic; fortunately these conditions are usually self-limiting. A decline in testicular
function probably contributes to the continuing bone loss and rising fracture rate in men over
70 years of age. A more obvious relationship is found in young men with overt hypogonadism;
this may require long-term treatment with testosterone.
b. Hyperthyroidism
Thyroxine speeds up the rate of bone turnover, but resorption exceeds formation. Osteoporosis
is quite common in hyperthyroidism, but fractures usually occur only in older people who
suffer the cumulative effects of the menopause and thyroid overload. In the worst cases
osteoporosis may be severe with spontaneous fractures, a marked rise in serum alkaline
phosphatase, hypercalcaemia and hypercalciuria. Treat ment is needed for both the
osteoporosis and the thyro toxicosis.
c. Multiple myeloma and carcinomatosis
Generalized osteoporosis, anaemia and a high ESR are characteristic features of myelomatosis
and metastatic bone disease. Bone loss is due to overproduction of local osteoclast-activating
factors. Treatment with bisphosphonates may reduce the risk of fracture.
d. Alcohol abuse
This is a common (and often neglected) cause of osteoporosis at all ages, with the added factor
of an increased tendency to falls and other injuries. Bone changes are due to a combination of
decreased calcium absorption, liver failure and a toxic effect on osteoblast function. Alcohol
also has a mild glucocorticoid effect.
e. Immobilization
The worst effects of stress reduction are seen in states of weightlessness; bone resorption,
unbalanced by formation, leads to hypercalcaemia, hypercalciuria and severe osteoporosis.
Lesser degrees of osteoporosis are seen in bedridden patients, and regional osteoporosis is
common after immobilization of a limb. The effects can be mitigated by encouraging mobility,
exercise and weightbearing.
f. Other conditions
There are many other causes of secondary osteoporosis, including hyperparathyroidism (which
is considered below), rheumatoid arthritis, ankylosing spondylitis and subclinical forms of
osteogenesis imperfecta. The associated clinical features usually point to the diagnosis
Bone biopsy
In the past, bone histomorphometry was commonly used to assess the severity of osteoporosis
before the advent of dual energy X-ray absorptiometry. Bone biopsies are now rarely
performed. In a highly select group of patients, bone biopsy performed and interpreted by an
experienced specialist is useful in establishing the underlying aetiology and appropriate therapy
of atypical cases if non-invasive methods have been inconclusive. Bone histomorphometry is
a specialist tool to diagnose and assess:
• osteomalacia
• renal bone disease
• bone turnover (to differentiate between low- and high-turnover osteoporosis) with
potential impact on therapeutic options.
In one specialist centre, 99 transiliac bone biopsies were performed over 14 years on ‘atypical’
cases of osteoporosis. This represented 0.003% of patients reviewed for bone-related
consultations. Bone marrow and trephine biopsy is only required to exclude an underlying
haematological cause for osteoporosis such as plasma cell dyscrasia, lymphoma or mastocyte
disorders which will require specific therapies.
 SHORT BOWEL SYNDROME
The normal human small intestine ranges between 3 and 8 m in length, depending on whether
measurement is made by radiologic or surgical techniques or at autopsy when the intestine may
be desicated. Short bowel syndrome is defined in adults as <200 cm of small intestine.
Although usually acquired because of one or more enterectomies, short bowel syndrome may
also be congenitally acquired. Nutrient, electrolyte, and fluid absorption is proportional to the
amount of residual intestine. The degree of intestinal function is better described in terms of
energy absorption/loss rather than length of residual intestine. Intestinal failure may be defined
as the inability to sustain adequate nutritional, electrolyte, or hydrational status in the absence
of specialized nutritional support. This requires an increase in oral intake because absorption
is compromised. Clinically, nutrient assimilation is a function of intake and absorption. As
such, some patients with short bowel syndrome will not have sufficient loss of functional
capacity as to develop intestinal failure. Significant individual variability in jejunal absorption
efficiency may be encountered.
The patients with the greatest risk for development of dehydration, generalized protein-calorie
malnutrition, and multiple nutrient deficiencies are those with a duodenostomy or jejunoileal
anastomosis and <35 cm of residual small intestine; jejunocolic or ileocoloic anastomosis, and
<60 cm of residual small intestine; or end jejunostomy with <115 cm of residual small intestine.
Those patients with residual colon in continuity will have enhanced energy and fluid
absorption.
Hence, such patients can tolerate greater loss of small intestine and retain their nutritional
autonomy.
Etiology
Short bowel syndrome may be a congenital or acquired condition. Infants may be born with
congenital jejunal or ileal atresia. Otherwise, short bowel syndrome results from surgical
resection of bowel. This is usually related to multiple resections for recurrent Crohn’s disease,
massive enterectomy made necessary because of a catastrophic vascular event such as
mesenteric arterial embolism, venous thrombosis, volvulus, trauma, or tumor resection in
adults, and, in children, gastroschisis, necrotizing enterocolitis (NEC), volvulus, and extensive
aganglionosis. Functional short bowel syndrome may also occur in cases of severe
malabsorption in which the bowel length is often intact. Such conditions may include chronic
intestinal pseudo-obstruction syndrome, refractory sprue, radiation enteritis, and congenital
villus atrophy. Severe nutrient and fluid malabsorption occurs following extensive small
intestinal resection. Patients with less than 100 cm of jejunum remaining generally have a net
secretory response to food.
Patients can be grouped into 2 distinct subgroups: those with intact colon in continuity and
those without colon in continuity. The colon becomes an important digestive organ in patients
with short bowel syndrome. Sodium, water, and some amino acids are absorbed in the colon as
well as energy from absorbed short-chain fatty acids.
Postresectional Adaptation
The intestine adapts as well to ensure more efficient absorption per unit length. Following
massive enterectomy, the intestine hypertrophies, and nutrient absorption becomes more
efficient. Although there are limited human data, observations in patients with massive
enterectomy as well as in the functional short bowel patient (JI-bypass) indicate that the
intestine lengthens some, but more importantly, diameter and villus height increase with a
resultant increase in absorptive surface. This process may evolve over 1 or 2 years. Patients
may be taught to adapt to their decreased absorption as well by dramatically increasing their
food intake (hyperphagia).
The presence or absence of the colon and ileocecal valve; location (jejunum versus ileum),
health, and length of residual bowel; mucosal blood flow; patient age; and comorbid conditions
such as Crohn’s disease, radiation enteritis, carcinoma, or pseudo-obstruction are important
determinants in the functional adaptation process and clinical outcome. Although the length of
remaining bowel necessary to prevent dependence on TPN is approximately 100 cm in the
absence of an intact and functional colon, or 60 cm in the presence of a completely functional
colon, the degree of adaptation and TPN dependence may be highly individualized.
Adaptation to full enteral nutrition has been reported with as little as 10 cm of residual intestine
in infants. Patients with a jejunostomy are at increased risk for TPN dependence, and those
with a jejunal-ileal anastomosis are less likely to be TPN dependent. Animal models have
suggested that enteroglucagon, glucagon peptide II, epidermal growth factor, growth hormone,
cholecystokinin, gastrin, insulin, and neurotensin are involved in postresection intestinal
adaptation. There are little data on the role of either increased endogenous hormonal release or
exogenous hormone supplementation during the intestinal adaptation phase in humans.
Residual ileum is able to adapt and to assume the role of macronutrient absorption when
jejunum has been resected. However, the specialized cells of the terminal ileum in which
vitamin B-12/intrinsic factor receptors are located and in which bile salts are reabsorbed cannot
be replaced by jejunal hypertrophy.
Medical Therapy of Short Bowel Syndrome
The goal of medical therapy is for the patient to resume work and a normal lifestyle, or as
normal of one as possible. This is undertaken via the use of specific measures to decrease
gradually the requirement for TPN and, at best, to eliminate its need. The most important
aspects of the medical management of the patient with short bowel syndrome are to provide
adequate nutrition, including both macro- and micronutrients, to prevent energy malnutrition
and specific nutrient deficiencies, to provide sufficient fluid to prevent dehydration, and to
correct and prevent acid-base disturbances. Most macronutrients, including carbohydrate,
nitrogen, and fat, are absorbed within the first 100 cm and up to 150 cm of jejunum.
Vitamins
Micronutrients often require supplementation. It is unusual for water-soluble vitamin
deficiencies to develop in short bowel patients in the absence of TPN (except in those who
have proximal jejunostomies or duodenostomies) because these are absorbed in the proximal
jejunum. Thiamine deficiency has been described, especially during a recent parenteral vitamin
shortage.
Patients may present with Wernicke’s encephalopathy, beriberi, and severe metabolic alkalosis.
Whole blood thiamine concentration may not be indicative of deficiency as it reflects recent
nutritional intake. Erythrocyte transketolase activity should be measured and empiric therapy
begun with 100 mg parenteral thiamine daily. Biotin deficiency has rarely been reported in
patients with short bowel syndrome. Scaly dermatitis, alopecia, lethargy, hypotonia, and lactic
acidosis have been described. Therapy consists of parenteral biotin supplemen-tation of 0.3–1
mg daily, although this is not commercially available in the United States. Vitamin B-12
supplementation is required (300 mcg/month subcutaneously) in patients who have had a >60-
cm terminal ileum resected. Folic acid is provided as a constituent of most oral and parenteral
multivitamins. Folate deficiency may develop in patients with proximal jejunal resections.
These patients should receive 1 mg folate daily.
Fat-soluble vitamin deficiency (A, D, and E) is more common in patients with short bowel
syndrome because of fat maldigestion related to decreased bile salt reabsorption and decreased
micelle formation. Cholestyramine may cause fat-soluble vitamin deficiency because of its
binding of bile salts. Night blindness and xerophthalmia have been described in short bowel
syndrome. If not recognized, vitamin A deficiency may progress to corneal ulceration and later
permanent visual loss may develop. The serum vitamin A concentration should be monitored
in patients who do not require parenteral vitamin supplementation. If a low serum vitamin A
concentration is detected, therapy should be started with 10,000–50,000 units daily,
administered either orally or parenterally.
Vitamin D deficiency manifests in osteomalacia. Usually, dietary intake is a relatively
unimportant source of vitamin D because the majority is endogenously synthesized from 7-
dehydrocholesterol via ultraviolet light. However, because enterohepatic circulation is
disrupted in patients who have undergone significant ileal resections, deficiency may result.
Vitamin E deficiency may manifest in hemolysis and various neurologic deficits. Because
serum vitamin E concentration reflects serum total lipid concentration, which may be low in
short bowel patients who have steatorrhea, low serum vitamin E concentration alone may not
be indicative of a deficient state; the serum vitamin E:total lipid ratio should be calculated.
Most vitamin K is synthesized by colonic bacteria (60%), although dietary intake accounts for
approximately 40% of requirements; deficiency is therefore uncommon in patients with intact
colon. However, vitamin K deficiency is frequent in patients who have no residual colon or
who have taken broad-spectrum antibiotics recently. The requirement is approximately 1 mg
daily. Vitamin K was not a constituent in adult multivitamins for TPN until recently, although
it has in children.