Review of bone physiology, hormonal involvement and
metabolic bone disease including osteoporosis and
hyperparathyroidism
Cara A. Swenson, MD
Introduction:
The skeleton is often thought of as an inert organ; however bone is constantly
undergoing remodeling and metabolic activity. The metabolic function is largely a
calcium and phosphate store and may contribute to buffering with changes in hydrogen
ion concentration. Constant remodeling is due to the production of matrix by osteoblasts,
maturation and mineralization of the matrix, and resorption of the mineralized matrix by
osteoclasts [1]. Further, multiple systemic hormones contribute to bone cell function
including parathyroid hormone, calcitriol, calcitonin, growth hormone, thyroid hormones
and glucocorticoids [4].
Hormonal Involvement:
Parathyroid hormone (PTH) is the most important regulator of calcium
homeostasis. PTH is a polypeptide secreted from the parathyroid gland. Secretion is
stimulated in a response to a decrease in concentration of ionized calcium [6]. The
hormone acts to increase serum calcium by three mechanisms: 1. stimulating bone
resorption (mediated by osteoclasts); 2. in the presence of vitamin D, enhancing intestinal
calcium and phosphate absorption; and 3. enhancing active renal calcium absorption [6].
Vitamin D3, a fat-soluble steroid produced in the skin and present in the diet, is
hydroxylated twice to form calcitriol. The most important action of calcitriol is to
enhance the availability of calcium and phosphate for new bone formation [6]. This is
done by increasing intestinal calcium and phosphorus absorption and promoting bone
mineralization [4].
Calcitonin has the transient effect of inhibiting osteoclasts and bone resorption.
Thyroid hormones and glucocorticoids stimulate bone resorption and formation. Excess
thyroid hormone in hyperthyroidism may lead to bone loss. Glucocorticoids are necessary
for the differentiation of osteoblasts and sensitize bone to regulators of bone remodeling
[4].
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Metabolic Bone Disease:
Metabolic bone disease refers to conditions in which there is a diffuse decrease in
bone density and strength secondary to an increase in bone resorption or a decrease in
bone formation. Two of these conditions include osteoporosis and hyperparathyroidism
[1].
Osteoporosis (the most common metabolic bone disease) leading to fractures is a
major public health issue. The definition of osteoporosis is low bone mass and disruption
of the normal architecture of bone leading to higher risk of fracture. More than 300,000
hip fractures occur annually in the United States leading to an annual cost exceeding $10
billion in the US alone. Lifetime costs (to an individual) of a hip fracture can be as high
as $81,000. This disease is highly prevalent in older postmenopausal women. In fact, in
this population of women, more than 50% will experience a fracture. It is also noticeably
present in older men [8].
Diagnosis of osteoporosis is typically made by T-score of less than -2.5 on a
DEXA scan. On a histologic level, the cortices are thinned and porous while the
trabeculae are fewer, thinner and less connected [1].
Two forms of osteoporosis exist: primary and secondary. Primary (also termed
involutional) refers to osteoporosis secondary to progressive loss of bone with increasing
age and may be divided into two types. Type 1 is related to a deficiency of estrogen and
is primarily a disease of postmenopausal women. Type 1 mostly affects trabecular bone
and may be responsible for wrist and vertebral fracture. Type 2 (senile osteoporosis) is
secondary to progressive bone loss after age 35 and affects cortical and trabecular bone
leading to fractures of the hip, pelvis and proximal humerus in elderly individuals. The
prevalence of hip fracture in the US by age 80 approaches 15%. Secondary osteoporosis
results from an underlying medical condition or medication (most commonly
corticosteroids) [1].
Risk fractures for osteoporosis include increasing age, family history of
osteoporosis in a first degree relative, cigarette smoking, low body weight, and personal
history of fracture after age 40. As mentioned above diagnosis is typically made by Tscore on DEXA scan less than -2.5 or history of fragility fracture regardless of T-score.
This condition has no clinical manifestations until there is a fracture. Fractures of
the vertebrae are the most common clinical manifestation of osteoporosis with most being
asymptomatic and diagnosed incidentally. Unfortunately, vertebral fractures are under
diagnosed and approximately 19 percent of women with one fracture will develop
another fracture within 1 year. Vertebral fractures may lead to significant pain, increased
thoracic kyphosis and height loss. As mentioned above, hip fractures, distal radial
fractures and humerus fractures may also occur [3].
Treatment for osteoporosis consists of calcium, vitamin D, weight bearing
exercise and pharmacologic treatment including estrogen and bisphosphonates.
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Unfortunately, recent studies indicate that although osteoporosis and associated fractures
are recognized as a significant problem, under diagnosis and under treatment are
common. A recent study by Burgener et al, interviewed older adults and found that the
term “osteoporosis” is well recognized; however, full understanding of the disease is
limited. The participants understood that the disease is serious but most didn’t recognize
themselves to be at risk [11]. Further, a recent review of the medical literature by
Solomon et al revealed that treatment for osteoporosis is suboptimal in that most patients
at high risk for fractures do not receive adequate treatment to prevent fractures. This
review also demonstrated that men and patients treated by generalists are at an especially
high risk of not receiving treatment. Patients who carry the diagnosis of osteoporosis and
those who are studied with bone densitometry are more likely to be treated with
medications [8]. These studies demonstrate that osteoporosis awareness is high but
patients often have an incomplete understanding of the disease and inadequate treatment
[11].
Hyperparathyroidism, another of the metabolic bone disorders, is characterized by
marrow fibrosis, expansion of osteoid surfaces and collections of osteoclasts with
resorptive surfaces. The disorder may be classified as primary or secondary.
Primary hyperparathyroidism presents as asymptomatic hypercalcemia, symptomatic
hypercalcemia during evaluation for clinical manifestations of the disease, or rarely with
bone disease. An etiology for primary hyperparathyroidism is determined in only a small
number of patients such as those exposed to radiation or those with the MENI gene.
Some of the pathologic processes often associated with primary disease include
parathyroid adenomas, carcinomas and glandular hyperplasia [3].
As mentioned above hyperparathyroidism (primary or secondary) may lead to
metabolic bone disease. Radiograph findings many include subperiosteal resorption,
resorption of the distal phalanges and tapering of the distal clavicle. Another important
feature of bone disease associated with hyperparathyroidism is demineralization that may
be demonstrated as osteopenia on radiographic evaluation. The diagnosis of osteoporosis
therefore should include evaluation for primary hyperparathyroidism. An elevated
parathyroid hormone in the serum in combination with hypercalcemia supports the
diagnosis. Treatment for primary disease in the setting of bone disease may be an
indication for parathyroidectomy [3].
Secondary hyperparathyroidism is a common manifestation in patients with a
tendency to retain phosphate such as those with a decreased glomerular filtration rate
(GFR). In fact, secondary hyperparathyroidism is almost universally present in patients
with chronic renal insufficiency [10]. As GFR decreases there is a reduction in the
filtered and excreted phosphate load. If intake remains the same the result is phosphate
retention and commonly the development of secondary hyperparathyroidism. Over time
exposure to high levels of PTH leads a serious bone disease termed osteitis fibrosa. This
condition is characterized by increased numbers of both osteoblasts and osteoclasts
ultimately leading to increased bone turnover and poor quality bone [9].
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Treatment of secondary hyperparathyroidism in patients with chronic kidney
disease (CKD) is aimed at tightly managing serum levels of calcium, phosphorus and
parathyroid hormone. According to the Kidney Disease Outcomes Quality Initiative
(K/DOQI) targets for these levels in patients with stage 5 CKD (GFR less than 15)
include goal PTH of 150-300 pg/ml, corrected calcium of 8.4-9.5 mg/dl and phosphorus
levels of 3.5-5.5 mg/dl [10]. In patients with stage 3 and 4 CKD (GFR between 15-59)
serum phosphate goal is 2.7-4.6 mg/dl. Further, the calcium phosphate product goal is
less than 55 in patients with stage 3, 4 or 5 CKD [9]. Maintaining the above serum levels
and preventing hyperphosphatemia is the mainstay of treatment and can be challenging.
Two modalities that have been used to avoid hyperphosphatemia include restricting
dietary phosphate intake and using agents to bind phosphate in the gut.
A goal of approximately 800 mg per day of phosphate is a level that patients may
find attainable. This can be done by limiting protein intake. This may be desirable in
patients with CKD to also slow the progression of disease, however, a large portion of
patients on hemodialysis are malnourished and require protein supplementation rather
than restriction. Patients faced with this may be encouraged avoid unnecessary dietary
phosphate such as diary products and vegetables. In addition to limiting intake lowering
phosphate may be achieved with phosphate binders. Many patients with CKD and all
patients on hemodialysis require oral phosphate binders. These typically consist of
sevelamer, calcium salts and aluminum hydroxide [2].
Conclusion:
The skeleton is a metabolically active organ undergoing constant metabolic
activity influenced by hormones including parathyroid hormone, calcitriol and calcitonin.
Metabolic bone disease occurs when there is a net loss in bone density. Osteoporosis is a
large public health problem resulting in significantly morbidity and mortality and health
costs. The condition is often underdiagnosed and treatment is underutilized. Further,
patients with a tendency to retain phosphate, especially those with chronic kidney
disease, are at significant risk of developing osteitis fibrosa, a condition of increased bone
turnover that is difficult to treat. As the understanding of bone remodeling and metabolic
activity expands new prospects for the management of these disorders will continue to
progress.
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REFERENCES:
1. Agus, Z. S: Overview of metabolic bone disease. Uptodate online
2. Cronin; Treatment of hyperphosphatemia in chronic renal failure. Uptodate online.
3. Fuleihan, G.E: Clinical manifestations of primary hyperparathyroidism. Uptodate
online
4. Raisz, L: Normal skeletal development and regulation of bone formation and
resporption. Uptodate online.
5. Rose and Henrich; Pathogenesis of renal osteodystrophy. Uptodate online.
6. Rose, B.D, Post, T.W: Clinical Physiology of Acid-Base and Electrolyte
Disorders 2001
7. Rosen, H.N, Drezner, M.K: Clinical manifestations and diagnosis of osteoporosis.
Uptodate online.
8. Solomon, D, Morris, C, Cheng, H, Cabrai, D, Katz, J, Finkelstein, J, Avorn, J:
Medication Use Patterns for Osteoporosis: An Assessment of Guidelines, Treatment
Rates, and Quality Improvement Interventions. Mayo Clin Pro. Feb 2005; 80(2):194-202
9. Steddon, S.J, Fan, S.L.S, Cunningham, J: New Prospects for the Management of Renal
Bone Disease. Nephron Clin Pract 2005; 99:c1-c7
10. Uribarri, J: K/DOQI Guidelines for Bone Metabolism and Disease in Chronic Kidney
Disease: Some Therapeutic Implications. Seminars in Dialysis 2004; 17(5): 349-350
11. Burgener M, Arnold M, Katz JN, Polinski JM, Cabral D, Avorn J, Solomon DH:
Older adults’ knowledge and beliefs about osteoporosis: results of semistructured
interviews used for the development of educational materials. J Rheumatol. 2005
Apr; 32 (4): 673-7.
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