Metabolic
Bone Disease Secondary Osteoporosis
Osteoporosis may occur as a
secondary problem in patients with a range of endocrine and other disorders
(Fig. 55a; Table 55.1). A high proportion of patients treated chronically with
glucocorticoids develop osteoporosis. It may develop in patients immobilized
for long periods, when bone resorption develops with consequent hypercalciuria
and hypercalcaemia, especially in younger patients in whom bone turnover is
normally rapid. Osteoporosis has been observed in astronauts, presumably due to
the loss of gravitational effects, although the aetiology of this phenomenon is
unknown. Hereditary disorders of collagen expression and metabolism may result
in osteoporosis. These include Ehlers–Danlos syndrome, homocysteinuria and
osteogenesis imperfecta.
The vast majority of patients
with osteoporosis have the primary condition but causes of secondary
osteoporosis should always be sought when undertaking clinical assessment.
Glucocorticoids and
osteoporosis Glucocorticoids,
used to treat inflammatory disorders, cause osteoporosis, affecting
predominantly the trabecular bone of the axial skeleton such that vertebral
fractures are more common than those of the hip. Glucocorticoids cause
osteoporosis through a wide variety of actions (Fig. 55b).
Direct actions. Glucocorticoids directly inhibit the
replication of osteoblast lineages and the biosynthesis of new osteoblast cells
and they induce apoptosis of osteoblasts, partially through their interactions
with growth factors such as the insulin-like growth factors. In addition,
glucocorticoids may directly decrease synthesis of osteocalcin, a component of
bone matrix, and stimulate the synthesis of collagenase-3, which breaks down
collagen types I and II, essential building blocks of bone. Furthermore,
glucocorticoids stimulate osteoclast activity directly, and possibly
indirectly, via secondary hyperparathyroidism.
Indirect actions. Glucocorticoids inhibit calcium absorption
from the GIT and increase renal excretion, which may contrib- ute to the
development of secondary hyperparathyroidism. Glucocorticoids are associated
with decreased plasma levels of estrogens and testosterone by suppressing
adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary
gland, thus resulting in suppression of adrenal androgen production.
Luteinizing hormone production is decreased with consequent lowering of both
estradiol and testosterone production in women and men respectively. Glucocorticoids
also inhibit growth hormone production. Patients with Cushing’s syndrome, which
is associated with excessive adrenal activity, may also be at risk of
osteoporosis and fractures.
Glucocorticoid therapy is a
major cause of rapid bone loss and primary preventive therapy with
bisphosphonates should be prescribed for every patient about to start a course
of steroid therapy for more than 3 months.
Other endocrine disorders
Hyperthyroidism can cause osteoporosis by the direct
action of thyroid hormone on bone resorption, since thyroid hormone is normally
associated with high bone turnover. Fractures are uncommon in hyperthyroidism
due to prompt diagnosis and treatment. Postmenopausal women with osteoporosis
and a history of hyperthyroidism are, however, at increased risk of hip
fractures. Type 1 diabetes mellitus is associated with mild osteopenia of
cortical bone, although there does not seem to be a high incidence of fractures
in these patients. Patients with Type 2diabetes mellitus, on the other hand, usually
have normal bone mass.
Heritable disorders
Several hundreds of mutations
of the collagen Type 1 gene have been reported, some of which may result in
defective osteoblast activity and result in brittle and fragile bones.
Osteogenesis imperfecta, for example, is caused by a mutation of the gene which
codes for Type 1 collagen, the main structural protein in bone matrix.
Different phenotypes may produce anything from a relatively mild condition to
one that is lethal to the embryo.
Immobilization and
osteoporosis
Patients who are immobilized
for prolonged periods, for example with neuromuscular disease or after spinal
injuries, are risk of developing osteoporosis. Prolonged immobility in bed may
reduce bone density by about 0.5% each month. Lumbar spine density may decrease
at a rate of about 1% each week, resulting in anything up to a 50% loss of bone
mass after a year. This is reversible, and mineralization of bone is initiated
when the patient becomes ambulatory again.
Prevention and treatment of
osteoporosis
Patients at risk from
osteoporosis should be given suitable lifestyle advice to maintain adequate
nutrition and normal body weight, to stop smoking and moderate excess alcohol
intake and to take as much weight-bearing exercise as possible. Patients with
established disease may benefit from hip-protectors if they are at risk of
falling, plus suitable occupational therapy assessment and walking aids.
Estrogen replacement therapy
at the menopause, with or without progestagens, has formed the mainstay of
treatment in women to prevent postmenopausal bone loss. However, recent data
from large observational studies have raised questions about the safety of HRT
in women over 50 years in terms of the increased risk of breast cancer. Estrogen
replacement should be offered to immediate women around the time of the
menopause for symptomatic relief but it is no longer recommended as first-line
therapy for the prevention of osteoporosis in women over 50 years. Younger
women with premature ovarian failure continue to receive estrogen up to 50
years of age.
Therapeutic intervention as
primary prevention may be offered to postmenopausal women with significant risk
factors depending upon their bone density. The bisphosphonates etidronate,
alendronate and risendronate have all been shown to prevent bone loss in the
spine and hip, both in healthy women at the menopause and in older patients
with established osteoporosis. Alendronate and risendronate have also both been
shown to reduce the fracture rate in women with osteoporosis. Strontium
ranelate may be offered to women intolerant of bisphosphonates. Following a
fracture, the same drugs may be offered or alternatives such as raloxifene
considered. Teriperatide, a PTH analogue, may be used where no other drug is
tolerated or effective.
Glucocorticoid-induced
osteoporosis should be prevented by primary prevention in patients starting
treatment by the coprescription of a bisphosphonate. In patients who have been
on prednisolone 7.5 mg daily or equivalent for 6 months or more, a dual
emission X-ray absorptiometry (DEXA) scan will establish the bone mineral
density and treatment can be given accordingly.
