Common postmenopausal osteoporosis PMO seen in white women is due to the polygenetic osteoporotic complex and there are no abnormal laboratory tests seen with it. There are many other causes of osteoporosis with very few being primary and a great many being secondary. Today idiopathic osteoporosis is and example of a primary disease. Several examples of secondary disorders that cause osteoporosis include such hypogonadism, hyperthyroidism, skeletal metastases, multiple myeloma, and anticonvulsant or oral corticosteroid use and alcohol abuse. These common causes are often already well known at the time osteoporosis is diagnosed but not always. Studies show that in white postmenopausal women with asymptomatic PMO 1 in 5 have secondary causes that can be diagnosed by lab testing. Around 30% of women and 55% of men with painful spine fractures have a secondary cause for osteoporosis. The most important causes to identify are the ones that can be treated because doing so often results in an improvement in the patient’s overall health, the osteoporosis and their response to its treatment. It is also important to find and treat these causes because doing so invariably improves the patient’s response to therapy for osteoporosis.
Once the laboratory anomaly is found, then a differential diagnosis is constructed around the finding. This evolves relating the lab test finding to diseases, conditions, or drugs that cause osteoporosis weighing the likelihood of each and then planning an efficient strategy to test for the presence of the ones that are thought to be most likely. This is an ongoing process of analysis, test and evaluate.
The purpose of having a laboratory evaluation after being diagnosed with osteoporosis is to determine:
- What the principal cause of the osteoporosis is
- To look for secondary conditions known to cause bone loss that make osteoporosis worse or more difficult to treat
- To ensure that current treatment with medications and hormones known to cause bone loss are not being prescribed in excess
- To determine the adequacy of calcium, magnesium, and vitamin D nutrition, absorption, and metabolism
- To establish the current kidney function by monitoring several blood salts like sodium and potassium that are regulated by the kidney
- To determine if health of the liver by measuring the levels of several key enzymes it uses for routine metabolism, proteins it makes, and byproducts it manages
- To check for high or low levels of serum calcium, magnesium or phosphorus and bicarbonate
- To establish if bone is remodeling slowly, moderately or rapidly
A targeted smart testing approach
To accomplish these goals, several tests, some common, and other rare are ordered on every patient seen at our center. There are many ways to evaluate people with osteoporosis, with no one-way being the right way. The method we use is to do a set of tests that is broad enough to identify all the important common treatable causes of osteoporosis and many of the rare ones. I do not advocate shotgun testing. It is costly, often results in false positives that result in more costs, and sometime exposes the patient to health risk for no benefit. Targeted smart testing is the route we follow.
An important guideline to bear in mind when interpreting test results is that there are no abnormal laboratory test due to osteoporosis. This means that any abnormal test found needs to be explained. On the other hand, almost every patient tested with has some abnormal lab tests, that is a fact of clinical life. The reason for the abnormality is usually obvious and has nothing to do with osteoporosis but never the less; it is the interpreting physician’s duty to explain each one.
|Basic Laboratory Evaluation for Patients Diagnosed with Osteoporosis|
|Complete Blood Count||
|Comprehensive Metabolic Panel||
|25 Hydroxyvitamin D3||
|Thyroid Stimulating Hormone||
|Highly Sensitive C-Reactive Protein||
|Erythrocyte Sedimentation Rate||
|24 hour Urine Calcium||
24 hr U Ca
|24 hour Urine Magnesium||
24 hr U mg
The complete blood count (CBC) provides a survey of the red and white blood cells counts and that provide insight into hematologic disorders that are characterized by increased cell turnover such as anemia and malignancies. Increased cellular turnover of hematologic cells within the bone marrow is associated with release of stimulatory growth factors in the microenvironment in close proximity to osteoclasts next door that are derived from the same hematologic stem cell line. Osteoclasts share receptors with their hematologic cousins and are stimulated by the same growth factors they are resulting in increased bone absorption and potentially osteoporosis. Some conditions associated with osteoporosis the CBC provides essential information about include: hemolytic anemia, thallasemia, chronic lymphocytic leukemia, Chronic myelogenous leukemia, myelofibrosis, Lymphomas, polycythemia, thrombocytosis, bulimia, anorexia
Diseases Causing Osteoporosis
The comprehensive metabolic profile (CMP) is the cornerstone of testing for clues to secondary causes for the patient’s osteoporosis. The underlying idea is to test in enough areas looking to indications of something amiss. When an anomaly is identified, then the search begins. An anomaly is a finding that does not fit in. It is a peculiarity, and exception to the common rule. The task of the clinician is to recognize an anomaly when he sees one and not merely skim over it without giving it a second thought. That requires mindfulness. The kidney function, liver function, calcium, serum electrolytes, bicarbonate, and a gross measurement of gamma globulin are all provided by in the CMP. Some conditions illuminated by the CBC: multiple myeloma, chronic kidney disease hepatic cirrhosis from all causes, metabolic acidosis, hyponatremia, hypophosphatemia, hypercalcemia, hypocalcemia, diabetes, hypophosphatasia, bulimia, malabsorption, pancreatitis, hyperparathyroidism, Addison’s disease
A parathyroid hormone level coupled with simultaneous serum calcium tells us if this calcium-regulating gland is operating normally. The intact PTH is used to diagnosis all forms of hyperparathyroidism and helps establish their causes i.e.; kidney, gut, diet, or parathyroid gland.
A thyroid stimulating hormone test (TSH) is obtained to check the health of the thyroid or to determine the adequacy of the patient’s current dose of thyroid hormone if she is on this hormone. It is essential to know what the osteoporosis patient’s TSH is because the hormone it regulates, thyroxine controls through T3 the rate of bone remodeling directly. High levels of T3 cause high remodeling rates leading to osteoporosis in those predisposed. It is common for Graves disease, the cause of hyperthyroidism in most women to be present for years before it is diagnosed but during this time women with this disease are making too much T3 and loosing bone. Ensuring that the patient’s TSH is normal means they are not hyperthyroid or if on treatment for hypothyroidism that the dose is correct.
ESR and HS-CRP Serum Markers of Inflammation
The erythrocyte sedimentation rate (ESR) and the highly sensitive cardio-reactive protein (HS-CRP) level are two tests of the inflammatory state of the body. The ESR is a measure of the level of antibodies in the blood and if elevated provides information about the presence of increased levels of these products of B-cells in response to an acute or chronic infection or inflammatory state. The HS-CRP is produced in the liver in response to the inflammatory T-cell cytokine IL-6. The higher the level of HS-CRP the higher the serum levels of IL-6. High systemic levels of IL-6 are characteristic of an active autoimmune disorders and this cytokine directly stimulates osteoclastic bone absorption promoting osteoporosis.
25 OH Vit D3
A 25 OH vitamin D3 level provides information about the adequacy of a patient’s vitamin D stores and if they have a low, normal, or elevated level of this hormone. This hormone is the only member of the DNA regulatory steroid hormone family that requires an outside energy source, UV light, activation step. That very interesting natural condition deserves considerable attention by a curious biologist and naturalist. The human population of the developed world lives inside and avoids the sun. Studies show 50% of whites are vitamin D deficient and 75% of African Americans are too. I test all my patients both osteoporosis and primary care for vitamin D adequacy and in my practice I see the similar findings. The majority of all human people living in advanced modern societies of all backgrounds are vitamin D deficient. Vitamin D plays an essential role in regulation of bone, in the management of calcium and magnesium metabolism, controlling the osteocytes and osteoblast function directly, stimulating enterocyte calcium absorption in the gut directly through its DNA receptor. That however is this hormone less important role in human health. Its principal function is regulation of the immune system. Vitamin D directly regulates over 1,000 genes or about 5% of the human genome. Obviously, it is critical to have a healthy level of vitamin D for many important reasons. Diseases associated with vitamin D deficiency include osteoporosis, osteomalacia, autoimmune disease, and many cancers including breast, colon, prostate, lung, and skin.
CTX and P1NP Bone Turnover Markers (BTM)
The serum CTX and P1NP are bone turnover markers. It is preferred that these always be drawn fasting in the morning about the same time each time to minimize the affect of biological variation on these results. The CTX is a bone absorption marker. It is a small piece of bone collagen that is all the remains after the osteoclasts breaks down a packet of bone using hydrochloric acid, TRAP and cathepsin K what remains behind is CTX. It circulates through the blood and is eventually excreted by the kidney.
The bone turnover markers are normal in PMO. If they are elevated, then this indicates a condition that drives rapid bone remodeling is present and is one of the sources of bone loss in the patient. These tests are very valuable for this reason diagnostically. One of the criticisms aimed at them is that they are not as accurate or precise as other lab tests used in diagnostic medicine like the serum calcium. This is true, but BTM are not used like that for diagnosis. Because of their lack of accuracy, it is appropriate to interpret them on as being low, medium, or high. This pass/fail system of interpretation avoids the nuance of specific thresholds and whether a patient is above or below one or not. A low or high marker level is plain as day. A BTM in the middle is too. Not as clear but useful still if it is closer to low or high. Almost all diseases causing osteoporosis cause high BTM levels. The autoimmune diseases and multiple myeloma are the big causes of high BTM that cause osteoporosis.
A low level of CTX indicates suppressed bone remodeling as seen with bisphosphonate therapy, a moderate or normal level is what is seen with normal remodeling when old bone is being removed but not excessively. A high level of CTX means that bone remodeling is accelerated and can be seen in several circumstances. In women with osteoporosis on no treatment, a high serum CTX means that she is loosing bone rapidly. The higher the CTX number the faster the bone loss rate. This is a valuable clue that there is a secondary cause of bone loss present that needs to be discovered because normal run of the mill PMO seen in white women is not characterized by remodeling that fast. A number of other situations are and many can be addressed if they are identified.
Bone markers are also useful for monitoring the patient’s response to therapy so obtaining the tests at the initial evaluation after the diagnosis has been made but before treatment has been initiated, provides a baseline against which to measure future progress. The marker changes in response to therapy much more rapidly than the bone density test.
Bone turnover markers are also useful to determine the effect and effectiveness of a patient’s current therapy. Is the prescribed therapy having the expected impact on the bone markers or not? If not, an adjustment is in order.
24 Hr Urine Calcium and Magnesium and Creatinine
The 24-hour urine collection for calcium and magnesium is the most difficult test we ask our patients to have and one of the most fruitful for sleuthing to causes of secondary osteoporosis. If the patient is not getting enough of these two minerals, that shows up best in this test because the kidney is told by the parathyroid gland that there is a shortage and to get all the mineral it can out of the urine. Under usual circumstances, there is no parathyroid hormone pressure on the kidney to perform. The kidneys filter the blood as usual, keeping the good and discarding the excess and waste. If for any reason the gut absorption of calcium or magnesium falls significantly, the blood level of calcium falls. The parathyroid gland, which constantly monitors the blood ionized calcium level second to second, detects it. PTH is released from the gland, goes to the kidney, and stimulates the renal tubule cells to pull out all the calcium that comes by them out of the urine and into the cell.
This results in low 24-hour urine calcium, a clue that something is wrong. The physician’s job is to work with the patient and figure out the cause of the low calcium from among the many know reasons. This is usually accomplished through Q&A but sometimes with more tests. Once the problem is found and remedied, the 24-hour urine is repeated to ensure that the problem has been correctly identified and addressed.
You may ask why go to the trouble of collecting that annoying 24 hour urine when you can simply do blood calcium test and directly see if I getting enough calcium or magnesium or not? It is necessary because both calcium and magnesium are primarily found within bone, locked up and out of circulation. They are intracellular minerals not extracellular. The free calcium and magnesium that is available is also intracellular for the most part with only a tiny percentage being extracellular. The intra- and extracellular levels of these two minerals are one of the most tightly regulated things within the human body. Too much or too little of either inside the cell or outside it is fatal. For this reason measurement of the blood calcium or magnesium only tells you about the extracellular level of these minerals but not very much about the much bigger intracellular pool and virtually nothing about whether or not you are absorbing these minerals from your diet or not. The 24-hour urine on the other hand more accurately reflects the true adequacy of the stores of the exchangeable pool of calcium and magnesium, the absorption of these minerals from the diet, and the adequacy of these minerals in the diet.
Renal Hypercalciuria vs. Absorptive Hypercalciuria
One of the most common secondary causes of osteoporosis found in my clinic is renal hypercalciuria. This common genetic condition is non-sex linked and inherited in an autosomal dominant pattern. It can also occur spontaneously. The patient or first his or her family members often but not always have a history of kidney stones. On the 24-hour urine, the calcium corrected for creatinine is elevated, usually above 300 mg/gm Cr. The other cause of high urine calcium is a high dietary intake of calcium +/- supplements that I call absorptive hypercalciuria. To differentiate the two conditions, the patient is asked to go on a calcium and vitamin free diet for one week and repeat the 24-hour urine calcium and creatinine. Normal people on a low calcium diet can remove almost all the calcium from the urine. I use the level of 100 mg/gm Cr to separate those malabsorbing calcium in the renal tubule from those who are not. Those above that level are designated as having renal hypercalciuria and those below absorptive hypercalciuria.
This is an important distinction to make because renal hypercalciuria is treatable with a thiazide diuretic. I prescribe Maxide 25 1 by mouth daily. It is important for the patient to understand that they have a genetic disorder; it is not going away, it is driving the osteoporosis; it is treatable with the diuretic but only if they take it. This will also help reduce their risk of having future kidney stones. I teach them about the condition and suggest they tell their relatives with kidney stones about it.
The simple urinalysis can hold a world of valuable information. It provides key data on the health and function of the kidney and clues to some of the rare but very important causes of osteoporosis. Diseases that cause osteoporosis that show up in a U/A include diabetes, multiple myeloma, systemic lupus, vasculitis, other autoimmune diseases.
That sums up the basis evaluation. From these tests, most causes of secondary osteoporosis can be detected if not directly indirectly leading to their subsequent diagnosis after additional testing.
Comprehensive Hormone Profile
Other tests bear on the diagnosis and management of men and women with osteoporosis and are routinely obtained at my center include a comprehensive hormone profile. Almost all authorities agree that men with osteoporosis require a hormone profile as part of their evaluation since hypogonadism is a recognized cause of osteoporosis in them. If they are found to be hypogonadal, they are offered hormone replacement therapy as part of an osteoporosis treatment strategy. While it is not debatable that menopause represents exactly the same condition in women our approach could not be more different. Why is our approach to these identical hormone deficiency states so different? This is an important Women’s Health issue and one that has much broader implications.
|Comprehensive Hormone Profile|
|Sex Hormone Binding Globulin||
Follow-Up Testing to Evaluate Anomalies Identified in the Initial Evaluation
There many tests available to evaluate anomalies found in the basic lab evaluation. It is usually safe to begin treatment before the work up is complete. For instance, it is common to take months or longer to confirm a case of suspected but early primary hyperparathyroidism. Some of the tests that I have found useful to further evaluate an abnormality are listed in the Secondary Laboratory Tests table.
|Secondary Laboratory Tests|
|RBC Folic acid||GI malabsorption|
|B12||GI malabsorption in stomach and ileum|
|Ferritin||GI malabsorption in duodenum|
|Serum Protein Electrophoresis||Multiple myeloma|
|Urine Protein Electrophoresis||Multiple myeloma light chains disease|
|Serum Immunofixation||Multiple myeloma|
|Urine Immunofixation||Multiple myeloma light chains disease|
|ANA screen with reflex to autoimmune panel||Auto-immune disease suggested by increase in ESR of HS-CRP|
|Celiac Disease Panel||GI malabsorption|
|Serum Amylase/Lipase||GI malabsorption due to chronic pancreatitis|
|Fasting AM Cortisone after bedtime dexamethasone suppression||Evaluation of Cushing’s Disease of the adrenal gland|