Bone turnover markers

Bones are constantly being remodelled to address the body’s calcium requirements and to repair microscopic damage.

The skeleton is replaced every 10 years in adults.

Compared with BMD, which is static and represents the net gain or loss of bone mass over the years two decades, BTM measurement are dynamic and reflect current bone metabolism.

Biochemical measures of bone turnover reflect rates of bone resorption or bone formation and can be found in blood or urine. 


Bone turnover markers may measure products of osteoblastic bone formation,  such as osteocalcin or bone-specific alkaline phosphatase, or they may measure collagen breakdown products that reflect bone resorption, such as pyridinolines or C- or N-terminal telopeptides. 

During skeletal growth, formation of bones rate exceeds resorption resulting in a net gain of bone.

Resorption rate exceeds formation rate later in life, particularly among estrogen deficient post menopausal females and all older people.

Prolonged bone loss needs to low bone mineral density (BMD) and eventually osteoporosis.


Bone turnover markers predict bone resorption and can be used to predict fracture risk and monitor treatment but should not be used to diagnose osteoporosis. 

Around 10% of the skeleton is involved in bone remodelling at any one time.

Removal of existing bone is mediated by osteoclastic bone resorption and replacement with new bone is mediated by osteoblastic bone formation.

Bone turnover markers are measures of bone turnover.

These bone turnover marker tests are part of routine clinical care, especially for osteoporosis.

Bone turnover marker tests are classified as markers of bone resorption or bone formation.

Resorption specific BTMs are typically breakdown products of type one collagen (N-telopeptide of type 1 collagen [NTX] and C-telopeptide of type 1 collagen [CTX], while formation specific markers include those reflecting type 1 Collagen synthesis (N-terminal pro peptide type1 procollagen[PINP], osteoblast enzymes-bone specific alkaline phosphatase, or bone matrix proteins-osteocalcin.

BTMs may be measured in blood and urine.

Bone active drugs and diseases influence BTMs rapidly, typically within 1 to 3 months, which is much sooner than observed with BMD.

Most antiresorptive osteoporosis medications, including bisphosphonates, promptly and substantially reduce concentrations of both resorption and formation BTM’s.

Anabolic osteoporosis treatments, such as teriparatide, and some diseases of skeletal metabolism such as hyperthyroidism, increase both resorption and formation BTM concentrations.

C-terminal telopeptide of type 1 collagen (CTX) is a marker for bone resorption, and procollagen type 1 N propeptide (P1NP) is a market for bone formation.

Bone is resorbed by osteoclasts.

Osteoblasts deposit organic matrix, or osteoid, and the osteoid then calcifies.

Bone is completely replaced after 3 months.

Bone resorption and bone formation are related, a marker from either group usually reflects bone turnover rate.

Bone comprises about two-thirds mineral and one-third osteoid, most of which is type 1 collagen.

During resorption of bone, fragments of type 1 collagen enter the circulation, and are then cleared in the urine.

The NTX test is based on an antibody against the N-terminal of collagen, including the cross-linking region.

CTX is based on an antibody to an octapeptide at the C-terminal end.

Bone formation markers may be enzymes or other proteins associated with osteoblast function, or may reflect the formation of type 1 collagen.

During bone formation, procollagen is cleaved at the N- and C- terminal ends.

Procollagen type I N-terminal propeptide (P1NP) reflects rate of new bone formation.

Alkaline phosphatase (ALP) is a marker of bone turnover and is useful in detecting conditions with gross elevations in bone turnover such as Paget disease.

Osteocalcin is a vitamin-K dependent protein.

Osteocalcin is attached to hydroxyapatite in calcified bone, and is a late marker of bone formation.

Bone turnover markers increase in proportion to fracture risk.

Bone turnover markers tend to be higher in patients with low bone density.

Very high marker levels are not typical of postmenopausal osteoporosis.

Following a fracture bone turnover markers may remain elevated for up to six months.

Additional causes for a high bone turnover: include hyperparathyroidism or hyperthyroidism, Paget disease, malignancy including myeloma, or advanced renal failure.

Bone turnover monitoring useful in  diseases with rapid and severe bone loss such as persons using chronic glucocorticoid therapy, with hyperparathyroidism or hypogonadism.

Bone turnover markers are typically altered within 1-3 months by bone active drugs, which is much sooner than observed with bone mineral density.

Most anti-resorptive osteoporosis medications, including bisphosphonates, promptly reduce concentration in both resorption and formation turnover markers.

Anabolic osteoporosis treatments, such as teriparatide, and some metabolic diseases such as hyperthyroidism increase both resorption and formation bone turnover marker concentrations.

Most bone turnover markers are spuriously increased by chronic kidney disease.

Bone mineral density is a common surrogate marker of osteoporosis treatment efficacy, however, it is not practical to repeat BMD at intervals shorter than 2 years.

Bone resorption markers typically fall by over 40% within 3 months of starting bisphosphonate therapy, and is followed by a reduction in bone formation markers over the next 6–12 months.

Denosumab produces a very rapid fall in resorption markers, which remain suppressed, with a slower fall in formation markers.

A small fall in resorption bone turnover markers can be seen with estrogen and other agents acting on the estrogen receptor.

Teriparatide stimulates new bone formation, and P1NP doubles within the first month of treatment and continue to increase over the first 6 months.

No consensus on how long bisphosphonate therapy should continue for osteoporosis.

It is proposed a drug holiday may be appropriate in lower risk patients after 5 years of continuous treatment.

Some propose using CTX to assess the risk of osteonecrosis of the jaw (ONJ) after invasive dental procedures in bisphosphonate treated patients.

Bone turnover markers vary from day-to-day.

A significant bone turnover marker change in results, is generally defined as 2.8 times the biological variation.

Most bone turnover markers are renally excreted, and therefore increase in renal failure.

There is a weak association between elevated bone turnover and accelerated bone loss.

Among older men and women, elevated resorption inflammation markersare associated with a modest increase the risk of several types of fracture, including hip and non-spine fracture, but this relationship is much weaker in those observed with low BMD.

Bone turnover is highest in the morning, decreasing significantly by lunchtime.

Meals suppress markers, particularly of bone resorption.

Most anti-resorptive and anabolic treatment trials report higher baseline bone turnover iis associated with greater increases in an BMD with treatment.

Serial measurements of bone turnover markers has no effect on osteoporosis medication adherence or persistence.

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