Endocrinology (part 5 – calcium and bone metabolism)

Some observations from chapter 6:

“*Osteoclasts – derived from the monocytic cells; resorb bone. *Osteoblasts – derived from the fibroblast-like cells; make bone. *Osteocytes – buried osteoblasts; sense mechanical strain in bone. […] In order to ensure that bone can undertake its mechanical and metabolic functions, it is in a constant state of turnover […] Bone is laid down rapidly during skeletal growth at puberty. Following this, there is a period of stabilization of bone mass in early adult life. After the age of ~40, there is a gradual loss of bone in both sexes. This occurs at the rate of approximately 0.5% annually. However, in ♀ after the menopause, there is a period of rapid bone loss. The accelerated loss is maximal in the first 2-5 years after the cessation of ovarian function and then gradually declines until the previous gradual rate of loss is once again established. The excess bone loss associated with the menopause is of the order of 10% of skeletal mass. This menopause-associated loss, coupled with higher peak bone mass acquisition in ♂, largely explains why osteoporosis and its associated fractures are more common in ♀.”

“The clinical utility of routine measurements of bone turnover markers is not yet established. […] Skeletal radiology[:] *Useful for: *Diagnosis of fracture. *Diagnosis of specific diseases (e.g. Paget’s disease and osteomalacia). *Identification of bone dysplasia. *Not useful for assessing bone density. […] Isotope bone scans are useful for identifying localized areas of bone disease, such as fracture, metastases, or Paget’s disease. […] Isotope bone scans are particularly useful in Paget’s disease to establish the extent and sites of skeletal involvement and the underlying disease activity. […] Bone biopsy is occasionally necessary for the diagnosis of patients with complex metabolic bone diseases. […] Bone biopsy is not indicated for the routine diagnosis of osteoporosis. It should only be undertaken in highly specialist centres with appropriate expertise. […] Measurement of 24h urinary excretion of calcium provides a measure of risk of renal stone formation or nephrocalcinosis in states of chronic hypercalcaemia. […] 250H vitamin D […] is the main storage form of vitamin D, and the measurement of ‘total vitamin D’ is the most clinically useful measure of vitamin D status. Internationally, there remains controversy around a ‘normal’ or ‘optimal’ concentration of vitamin D. Levels over 50nmol/L are generally accepted as satisfactory and values <25nmol/L representing deficiency. True osteomalacia occurs with vitamin D values <15 nmol/L. Low levels of 250HD can result from a variety of causes […] Bone mass is quoted in terms of the number of standard deviations from an expected mean. […] A reduction of one SD in bone density will approximately double the risk of fracture.”

[I should perhaps add a cautionary note here that while this variable is very useful in general, it is more useful in some contexts than in others; and in some specific disease process contexts it is quite clear that it will tend to underestimate the fracture risk. Type 1 diabetes is a clear example. For more details, see this post.]

“Hypercalcaemia is found in 5% of hospital patients and in 0.5% of the general population. […] Many different disease states can lead to hypercalcaemia. […] In asymptomatic community-dwelling subjects, the vast majority of hypercalcaemia is the result of hyperparathyroidism. […] The clinical features of hypercalcaemia are well recognized […]; unfortunately, they are non-specific […] [They include:] *Polyuria. *Polydipsia. […] *Anorexia. *Vomiting. *Constipation. *Abdominal pain. […] *Confusion. *Lethargy. *Depression. […] Clinical signs of hypercalcaemia are rare. […] the presence of bone pain or fracture and renal stones […] indicate the presence of chronic hypercalcaemia. […] Hypercalcaemia is usually a late manifestation of malignant disease, and the primary lesion is usually evident by the time hypercalcaemia is expressed (50% of patients die within 30 days).”

“Primary hyperparathyroidism [is] [p]resent in up to 1 in 500 of the general population where it is predominantly a disease of post-menopausal ♀ […] The normal physiological response to hypocalcaemia is an increase in PTH secretion. This is termed 2° hyperparathyroidism and is not pathological in as much as the PTH secretion remains under feedback control. Continued stimulation of the parathyroid glands can lead to autonomous production of PTH. This, in turn, causes hypercalcaemia which is termed tertiary hyperparathyroidism. This is usually seen in the context of renal disease […] In majority of patients [with hyperparathyroidism] without end-organ damage, disease is benign and stable. […] Investigation is, therefore, primarily aimed at determining the presence of end-organ damage from hypercalcaemia in order to determine whether operative intervention is indicated. […] It is generally accepted that all patients with symptomatic hyperparathyroidism or evidence of end-organ damage should be considered for parathyroidectomy. This would include: *Definite symptoms of hypercalcaemia. […] *Impaired renal function. *Renal stones […] *Parathyroid bone disease, especially osteitis fibrosis cystica. *Pancreatitis. […] Patients not managed with surgery require regular follow-up. […] <5% fail to become normocalcaemic [after surgery], and these should be considered for a second operation. […] Patients rendered permanently hypoparathyroid by surgery require lifelong supplements of active metabolites of vitamin D with calcium. This can lead to hypercalciuria, and the risk of stone formation may still be present in these patients. […] In hypoparathyroidism, the target serum calcium should be at the low end of the reference range. […] any attempt to raise the plasma calcium well into the normal range is likely to result in unacceptable hypercalciuria”.

“Although hypocalcaemia can result from failure of any of the mechanisms by which serum calcium concentration is maintained, it is usually the result of either failure of PTH secretion or because of the inability to release calcium from bone. […] The clinical features of hypocalcaemia are largely as a result of neuromuscular excitability. In order of  severity, these include: *Tingling – especially of fingers, toes, or lips. *Numbness – especially of fingers, toes, or lips. *Cramps. *Carpopedal spasm. *Stridor due to laryngospasm. *Seizures. […] symptoms of hypocalcaemia tend to reflect the severity and rapidity of onset of the metabolic abnormality. […] there may be clinical signs and symptoms associated with the underlying condition: *Vitamin D deficiency may be associated with generalized bone pain, fractures, or proximal myopathy […] *Hypoparathyroidism can be accompanied by mental slowing and personality disturbances […] *If hypocalcaemia is present during the development of permanent teeth, these may show areas of enamel hypoplasia. This can be a useful physical sign, indicating that the hypocalcaemia is long-standing. […] Acute symptomatic hypocalcaemia is a medical emergency and demands urgent treatment whatever the cause […] *Patients with tetany or seizures require urgent IV treatment with calcium gluconate […] Care must be taken […] as too rapid elevation of the plasma calcium can cause arrhythmias. […] *Treatment of chronic hypocalcaemia is more dependent on the cause. […] In patients with mild parathyroid dysfunction, it may be possible to achieve acceptable calcium concentrations by using calcium supplements alone. […] The majority of patients will not achieve adequate control with such treatment. In those cases, it is necessary to use vitamin D or its metabolites in pharmacological doses to maintain plasma calcium.”

“Pseudohypoparathyroidism[:] *Resistance to parathyroid hormone action. *Due to defective signalling of PTH action via cell membrane receptor. *Also affects TSH, LH, FSH, and GH signalling. […] Patients with the most common type of pseudohypoparathyroidism (type 1a) have a characteristic set of skeletal abnormalities, known as Albright’s hereditary osteodystrophy. This comprises: *Short stature. *Obesity. *Round face. *Short metacarpals. […] The principles underlying the treatment of pseudohypoparathyroidism are the same as those underlying hypoparathyroidism. *Patients with the most common form of pseudohypoparathyroidism may have resistance to the action of other hormones which rely on G protein signalling. They, therefore, need to be assessed for thyroid and gonadal dysfunction (because of defective TSH and gonadotrophin action). If these deficiencies are present, they need to be treated in the conventional manner.”

“Osteomalacia occurs when there is inadequate mineralization of mature bone. Rickets is a disorder of the growing skeleton where there is inadequate mineralization of bone as it is laid down at the epiphysis. In most instances, osteomalacia leads to build-up of excessive unmineralized osteoid within the skeleton. In rickets, there is build-up of unmineralized osteoid in the growth plate. […] These two related conditions may coexist. […] Clinical features [of osteomalacia:] *Bone pain. *Deformity. *Fracture. *Proximal myopathy. *Hypocalcaemia (in vitamin D deficiency). […] The majority of patients with osteomalacia will show no specific radiological abnormalities. *The most characteristic abnormality is the Looser’s zone or pseudofracture. If these are present, they are virtually pathognomonic of osteomalacia. […] Oncogenic osteomalacia[:] Certain tumours appear to be able to produce FGF23 which is phosphaturic. This is rare […] Clinically, such patients usually present with profound myopathy as well as bone pain and fracture. […] Complete removal of the tumour results in resolution of the biochemical and skeletal abnormalities. If this is not possible […], treatment with vitamin D metabolites and phosphate supplements […] may help the skeletal symptoms.”

Hypophosphataemia[:] Phosphate is important for normal mineralization of bone. In the absence of sufficient phosphate, osteomalacia results. […] In addition, phosphate is important in its own right for neuromuscular function, and profound hypophosphataemia can be accompanied by encephalopathy, muscle weakness, and cardiomyopathy. It must be remembered that, as phosphate is primarily an intracellular anion, a low plasma phosphate does not necessarily represent actual phosphate depletion. […] Mainstay [of treatment] is phosphate replacement […] *Long-term administration of phosphate supplements stimulates parathyroid activity. This can lead to hypercalcaemia, a further fall in phosphate, with worsening of the bone disease […] To minimize parathyroid stimulation, it is usual to give one of the active metabolites of vitamin D in conjunction with phosphate.”

“Although the term osteoporosis refers to the reduction in the amount of bony tissue within the skeleton, this is generally associated with a loss of structural integrity of the internal architecture of the bone. The combination of both these changes means that osteoporotic bone is at high risk of fracture, even after trivial injury. […] Historically, there has been a primary reliance on bone mineral density as a threshold for treatment, whereas currently there is far greater emphasis on assessing individual patients’ risk of fracture that incorporates multiple clinical risk factors as well as bone mineral density. […] Osteoporosis may arise from a failure of the body to lay down sufficient bone during growth and maturation; an earlier than usual onset of bone loss following maturity; or an rate of that loss. […] Early menopause or late puberty (in ♂ or ♀) is associated with risk of osteoporosis. […] Lifestyle factors affecting bone mass [include:] *weight-bearing exercise [increase bone mass] […] *Smoking. *Excessive alcohol. *Nulliparity. *Poor calcium nutrition. [These all decrease bone mass] […] The risk of osteoporotic fracture increases with age. Fracture rates in ♂ are approximately half of those seen in ♀ of the same age. An ♀ aged 50 has approximately a 1:2 chance [risk, surely… – US] of sustaining an osteoporotic fracture in the rest of her life. The corresponding figure for a ♂ is 1:5. […] One-fifth of hip fracture victims will die within 6 months of the injury, and only 50% will return to their previous level of independence.”

“Any fracture, other than those affecting fingers, toes, or face, which is caused by a fall from standing height or less is called a fragility (low-trauma) fracture, and underlying osteoporosis should be considered. Patients suffering such a fracture should be considered for investigation and/or treatment for osteoporosis. […] [Osteoporosis is] [u]sually clinically silent until an acute fracture. *Two-thirds of vertebral fractures do not come to clinical attention. […] Osteoporotic vertebral fractures only rarely lead to neurological impairment. Any evidence of spinal cord compression should prompt a search for malignancy or other underlying cause. […] Osteoporosis does not cause generalized skeletal pain. […] Biochemical markers of bone turnover may be helpful in the calculation of fracture risk and in judging the response to drug therapies, but they have no role in the diagnosis of osteoporosis. […] An underlying cause for osteoporosis is present in approximately 10-30% of women and up to 50% of men with osteoporosis. […] 2° causes of osteoporosis are more common in ♂ and need to be excluded in all ♂ with osteoporotic fracture. […] Glucocorticoid treatment is one of the major 2° causes of osteoporosis.”


February 22, 2018 Posted by | Books, Cancer/oncology, Diabetes, Epidemiology, Medicine, Nephrology, Neurology, Pharmacology | Leave a comment