Bone is removed and replaced all the time, and bone mass stays steady while removal and replacement balance, as the pathophysiology note explained. In primary osteoporosis that balance tips with age and with the loss of estrogen after the menopause. The steep fall in bone mass after the menopause comes from the loss of estrogen, as the pathophysiology note explained.
Most osteoporosis is primary, and no separate cause needs to be found. In a substantial minority of patients, though, bone loss is driven by another disease, a deficiency or a drug. This is secondary osteoporosis. A second force tips the same balance, either by speeding removal or by blocking replacement. So there is one balance and two kinds of push, and the focus is the second kind: the driver that has to be found.
Why does finding the cause matter?
If a second force is driving the loss, then a second force can be treated. Identifying the cause matters because treating it can stop bone loss. Some causes, such as multiple myeloma, also carry consequences of their own, beyond the bone. The causes come in groups.
What kinds of cause are there?
So the question is which drivers exist, and they fall into groups: lifestyle, inherited disorders, endocrine disease, digestive disease, blood disease, rheumatic and neurological disease, and drugs. We take them group by group.
Which lifestyle habits remove bone?
The first group is the one a person can change, and it works through diet and through the bone cells. The lifestyle causes are:
- low calcium intake
- vitamin D deficiency
- alcohol excess
- excess vitamin A
- high salt intake
- inadequate physical activity
- frequent falling
Alcohol seems to lower bone formation. Laboratory studies show that ethanol shifts stem cells in the marrow toward fat cells instead of bone-forming osteoblasts, so fewer osteoblasts are made.
Excess vitamin A acts on both sides of the balance. Retinoic acid raises the formation of RANKL, so more osteoclasts form. It also lowers the markers that osteoblasts need to mineralise bone.
Inadequate physical activity matters because bone senses load through its osteocytes, as the pathophysiology note explained.
Which inherited disorders weaken bone?
The lifestyle group is acquired; the inherited group is present from birth. The genetic causes are osteogenesis imperfecta, Marfan syndrome, homocystinuria, hypophosphatasia, cystic fibrosis, idiopathic hypercalciuria, glycogen storage diseases, Riley-Day syndrome, Menkes steely hair syndrome and androgen insensitivity.
How do hormone excesses and deficiencies remove bone?
The endocrine causes are hypogonadism, hyperthyroidism, hyperparathyroidism, Cushing’s syndrome, panhypopituitarism, anorexia nervosa, premature menopause and obesity. Endocrine causes are common and often treatable.
Hyperthyroidism raises bone turnover. In states of thyroid dysfunction, thyroid hormone can damage bone structure, so too much of it can remove bone. Hyperparathyroidism increases resorption, because parathyroid hormone acts on bone to release calcium, as the pathophysiology note explained.
How do glucocorticoids remove bone?
Cushing’s syndrome produces the same effect as therapeutic glucocorticoids, so cortisol excess is the endocrine cause that copies a drug. Glucocorticoids harm bone by several routes at once, and the pathophysiology note explained how the loss unfolds over time. Cortisol excess acts by the same routes.
Because the routes act at once, bone loss begins within the first few months of treatment. The drug threshold is more than 5 mg prednisone or equivalent for more than 3 months. Glucocorticoid excess is the second most common cause of low bone mass in the general population.
Other medications also cause bone loss:
- anticonvulsants
- long-term heparin
- excess thyroid hormone
- GnRH agonists
- aromatase inhibitors
- lithium
- depo-medroxyprogesterone
- tacrolimus
- proton pump inhibitors
- selective serotonin reuptake inhibitors
How does gut disease remove bone?
Glucocorticoids act on bone directly; the gut acts by lowering what bone is given. The gastrointestinal and hepatic causes are celiac disease, malabsorption, chronic liver disease, primary biliary cirrhosis and pancreatic disease.
In celiac disease, villous atrophy flattens the gut lining and lowers the absorption of nutrients. Calcium and vitamin D are among the micronutrients lost, so bone loses its supply. Malabsorption and celiac disease are easy to miss, because they lower absorption of calcium and vitamin D without obvious gastrointestinal symptoms.
How can a blood cancer look like osteoporosis?
The gut disease lowers the calcium and vitamin D that bone receives; the blood disease changes the cells in the bone. The hematologic causes are multiple myeloma, lymphoma, systemic mastocytosis, thalassemia and hemophilia.
Myeloma is an imbalance. Its cells drive bone removal and suppress bone formation, so bone is destroyed faster than it is rebuilt. In mastocytosis, mast cell mediators such as histamine act on osteoclasts and raise bone removal. Either disease can produce vertebral fractures that look osteoporotic. Myeloma therefore enters the differential of any patient presenting with these conditions.
Which other chronic diseases remove bone?
The blood diseases act on the marrow; the next group of chronic diseases affects many systems at once. It covers rheumatic and neurological disease and other chronic conditions:
- rheumatoid arthritis
- ankylosing spondylitis
- muscular dystrophy
- spinal cord injury
- immobilisation
- epilepsy
- chronic obstructive pulmonary disease
- congestive heart failure
- parenteral nutrition
- hyponatremia
- amyloidosis
- previous fracture in adulthood
- HIV/AIDS
How do the causes differ in men?
The pattern in men differs from that in women. The commonest secondary causes in men are glucocorticoid excess, hypogonadism and alcohol excess. Estradiol acts on the male skeleton as well as the female, as the pathophysiology note explained.
A proportion of men have idiopathic osteoporosis, in which no cause is found. In this group bone formation is low and IGF-I is low. IGF-I helps osteoblasts differentiate, so less IGF-I would be expected to mean less bone formation. That link is proposed, not a proven cause.
What does a Z-score add?
Where no cause is found, the scan result has to be read against what is expected for age and sex. The Z-score is the number of standard deviations by which bone mineral density differs from the mean for the patient’s own age and sex. It is sometimes used as a prompt to look for a secondary cause when it lies more than 2 standard deviations below that mean. This criterion is not universally accepted.
What clues point to a specific cause?
The body can also show clues to a specific cause. The diagnosis note taught the physical signs. Three clues suggest a specific cause:
- an enlarged thyroid gland
- atrophic testicles
- blue sclera combined with yellow-brown teeth and hearing loss
Which blood tests screen for treatable causes?
A short list of laboratory tests is used to screen for treatable causes.
What do the blood count and ESR suggest?
The first screen is the blood count and the ESR. On the complete blood count and ESR, anemia suggests malnutrition and a raised ESR suggests multiple myeloma.
What do calcium, phosphate and vitamin D show?
Calcium and phosphate are the next to read, since the gut and hormone causes act on them.
- Serum calcium: hypocalcemia suggests vitamin D deficiency. Hypercalcemia suggests vitamin D intoxication, primary or secondary hyperparathyroidism, thyrotoxicosis, renal failure or Paget’s disease.
- Serum phosphate: hypophosphatemia suggests primary or secondary hyperparathyroidism, or vitamin D deficiency.
- A raised alkaline phosphatase suggests healing fractures, Paget’s disease or osteomalacia.
- A low 25-OH vitamin D suggests low vitamin D stores. Values of 30-50 ng/ml are often taken as optimal, though there is no consensus.
What do kidney, liver and thyroid tests show?
Organ tests check the kidney, the liver and the thyroid. A raised creatinine suggests chronic kidney disease, a common cause of secondary hyperparathyroidism and skeletal disease. A low TSH suggests hyperthyroidism, which increases bone turnover. Raised liver enzymes suggest chronic liver disease.
What do protein and urine tests show?
Protein and urine tests look for the blood disease and the kidney. Proteinuria suggests multiple myeloma or chronic kidney disease. An M component on serum protein electrophoresis and an abnormal free kappa/lambda ratio suggest multiple myeloma. Hypercalciuria on 24-hour urine calcium suggests a renal leak of calcium (renal), excess skeletal loss (resorptive) or high gut absorption (absorptive).
What do antibody and hormone tests show?
The last screen uses antibody and hormone tests for the gut, the adrenal gland and the gonads. Positive anti-EMA and anti-tTG suggest celiac disease. Failure to suppress on the dexamethasone suppression test suggests Cushing’s syndrome. Low testosterone, total and free, suggests hypogonadism in men, and estradiol acts on the male skeleton as the pathophysiology note explained.
Can treating the cause repair the bone?
Once the cause is found, the next question is what happens to the bone itself. Finding a secondary cause does not always remove the need for treatment of the skeleton itself. Correcting the cause may reduce fracture risk, but the patient can still be left with bone loss after the cause is corrected. In celiac disease, for example, a gluten-free diet improves bone density without always normalising it, even after the gut lining recovers, so bone lost earlier can remain. And some causes, such as continued glucocorticoid therapy, have to be managed while the drug is still required.
If the bone has already been lost, what is done to rebuild its strength?