Background
Bone Turnover Markers
Degradation products generated during bone resorption and enzymes and proteins released during bone formation must be measured to perform biochemical monitoring of bone metabolism.
There are currently several biochemical markers that enable a precise and sensitive evaluation of the skeleton’s pace of bone production and resorption.
Bone Formation Markers
Alkaline phosphatase has been used as a bone metabolism marker in clinical settings for several years. In people with normal liver function, the liver and bone account for around half of the total alkaline phosphatase activity.
Specificity and sensitivity have increased with the development of immunoassay-based indicators that use monoclonal antibodies that target the bone-specific isoform of alkaline phosphatase.
The resorption markers show the suppression once antiresorptive medication begins as the coupling process returns to normal. The resorption markers show the suppression once antiresorptive medication starts as the coupling process returns to normal.
Due to its correlation with the rate of bone production, serum osteocalcin is regarded as a particular indicator of osteoblast function.
There are limits to using this diagnostic because of the ensuing heterogeneity of the osteocalcin fragments in the serum. The circadian pattern of osteocalcin levels is demonstrated by a decrease in the morning and a slow rise to a high after midnight.
Serum levels show the anticipated changes in bone production after surgical and therapeutic intervention, and they are higher in patients with illnesses that have a high bone turnover rate.
N- and C-terminal extensions found in procollagen type 1 are eliminated by proteases when procollagen is converted to collagen.
Anti-P1NP antibodies are employed in radioimmunoassay or enzyme-linked immunosorbent assay (ELISA) to identify the trimeric structure of P1NP.
Bone Resorption Markers
The breakdown products from the enzymatic hydrolysis of type 1 collagen, especially peptides associated with regions of cross-linking with pyridinoline (PYD), are the most helpful indicators of bone resorption.
Over 90% of the protein in bone is collagen type 1 that released collagen fragments would be the source of many bone indicators. When bone breaks down, it is released into the serum and ends up in the urine in both bound and free forms.
Both PYD and DPD measurements are unaffected by the breakdown of freshly generated collagens and are not influenced by dietary sources.
The ratio of these two cross-links in bone is comparable to the PYD-to-DPD ratio in urine indicating that both cross-links are mostly sourced from bone.
Several groups have created tests based on antibodies produced against isolated collagen peptides containing cross-links, as an alternative to use the cross-links as markers.
A patient with Paget disease has a urine pool of collagen cross-links that the monoclonal antibody used for the NTX assay targets.
The best indicators for evaluating bone resorption are thought to be the pyridinium cross-links and the collagen telopeptides involving the cross-linking sites.
Rarely do glycoproteins or non-collagenous proteins have enough specificity for bone to be regarded as a possible indication. The mineralization of recently deposited bone matrix and/or the calcification of extra skeletal tissues are believed to be facilitated by bone sialoprotein (BSP).
An antibody capture activity assay for tartrate-resistant acid phosphatase 5b as a bone resorption marker has been made easier by the finding that the type 5b isotype is selective for bone osteoclasts.
Predicting Future Bone Loss
Rapid bone loss increases the risk of fracture in later life for patients with a given BMD. Antiresorptive medications should be used as a preventative treatment for patients who are at risk for osteoporosis due to low bone mineral density or elevated marker levels.
Prospective studies that have examined the connection between biochemical indicators of bone turnover and the rate of bone loss have produced inconsistent findings due to several technical difficulties.
For women having baseline indicators, they separated them into groups with the fastest bone loss (>2.2%/y) and the slowest (<0.4%).
According to Gutierrez-Buey et al., women who had lower trabecular bone scores and greater baseline levels of serum bone turnover indicators had lower BMD as they entered menopause.
Collagen type 1 cross-linked C-telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) levels were higher in women with osteopenia or osteoporosis at follow-up than in women with normal bone mass.
The baseline urine collagen type 1 cross-linked N-telopeptide (NTX) or other measures did not correlate with future hip or spine bone mineral density in a subset analysis of an alendronate trial.
The condition of the adult skeleton’s remodelling units can be inferred from baseline indicators of bone turnover. Without treatment, the degree of bone loss in both younger and older postmenopausal women can be predicted by resorption and formation markers.
Assessment of Fracture Risk
With dual-energy x-ray absorptiometry (DXA), bone mineral density (BMD) can be measured with sufficient precision to determine the amount of bone mass.
BMD has been shown to be strongly correlated with the risk of hip, spine, and forearm fractures in several prospective studies.
Serum osteocalcin and bone alkaline phosphatase levels did not significantly correlate with the incidence of hip fractures during a 2-year follow-up in the large cohort of elderly women in France (EPIDOS).
Urinary and serum levels of C-telopeptide of type 1 collagen (CTX) or urinary free deoxypyridinoline (DPD) above the typical premenopausal range were consistently linked to bone resorption and a roughly two-fold increased risk.
Treatment Paradigm
Dual-energy x-ray absorptiometry (DXA) evaluation of bone mineral density (BMD) is a commonly utilized surrogate indicator of treatment effectiveness in clinical studies.
It is not suitable to use DXA to monitor therapy when using medications like nasal calcitonin or raloxifene, which cause considerably lower improvements in BMD.
It is possible to determine if a patient is responding to treatment with strong bisphosphonates like alendronate and risedronate by performing a BMD measurement two years after starting treatment.
DXA might not show all responders in the first year of treatment, as is the case with all treatments. The technique’s comparatively poor signal-to-noise ratio makes it impossible to distinguish responders from non-responders quickly (within months).
Failure to react could be the result of noncompliance, inadequate drug absorption in the intestines, additional bone loss-causing variables, or other unknown causes. Using bone markers to track osteoporosis treatment may also improve compliance.
Monitoring bisphosphonate therapy with bone marker measurements at baseline and at three and six months can increase therapy compliance by 20% at one year according to research.
The Multiple Outcomes of Raloxifene Evaluation (MORE) trial found that improvements in bone turnover markers were more closely associated with fracture risk with raloxifene medication than improvements in bone mineral density.
Because of its comparable diagnostic accuracy to P1NP and CTX, tartrate-resistant acid phosphatase type 5b (TRACP5b) has been proposed for the monitoring of patients receiving oral bisphosphonates and zoledronate
